Glossary

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A


Active Transport
Carriage of a solute across a biological membrane from low to high concentration that requires the expenditure of (metabolic) energy. If the process uses chemical energy, such as from adenosine triphosphate (ATP), it is termed primary active transport. Secondary active transport involves the use of an electrochemical gradient. Active transport uses energy, unlike passive transport, which does not use any energy. Active transport involves the use of proteins that don’t just passively facilitate the transport of substances across the cell membrane, but require the use of cellular energy (usually ATP) to actively pump substances into or out of the cell.

Address-message concept
Compounds in which part of the molecule is required for binding (address) and part for the biological action (message).

Adenosine Triphosphate (ATP)
Major carrier of chemical energy in the cells of all living things on this planet. A ribonucleoside 5`-triphosphate functioning as a phosphategroup donor in the energy cycle of the cell, ATP contains three phosphate/oxygen molecules linked together. When a phosphatephosphate bond in ATP is broken (hydrolyzed), the energy produced can be used by the cell to carry out its functions. Thus, ATP serves as the universal medium of biological energy storage and exchange in living cells.

Adjudication process
A process that reviews all evidence and hears all arguments in order to come to a final decision.

ADME
Abbreviation for Absorption, Distribution, Metabolism, Excretion. (See also Pharmacokinetics; Drug disposition).

ADMET or ADME/Tox
Acronym for Absorption, Distribution (within the body), Metabolism, Elimination, Toxicity of pharmaceuticals.

Adverse events
Any exaserbation or untoward change in a patient’s or subject’s baseline condition.  An adverse event may or may not be caused by a study drug.

Affinity
Tendency of a molecule to associate with another. The affinity of a drug is its ability to bind to its biological target (receptor, enzyme, transport system, etc.) For pharmacological receptors it can be thought of as the frequency with which the drug, when brought into the proximity of a receptor by diffusion, will reside at a position of minimum free energy within the force field of that receptor. For an agonist (or for an antagonist) the numerical representation of affinity is the reciprocal of the equilibrium dissociation constant of the ligand-receptor complex denoted Ka.

Agonist
Endogenous substance or a drug that can interact with a receptor and initiate a physiological or a pharmacological response characteristic of that receptor (contraction, relaxation, secretion, enzyme activation, etc.). A partial agonist binds to the receptor producing a limited biological effect.

Allosteric binding sites
Contained in many enzymes and receptors. An allosleric binding site on a receptor is different from the normal binding site for the natural ligand. When a drug binds to an allostcric binding site, it modifies the shape and action of the receptor and can affect the binding of the normal ligand. As a consequence of the binding to allosteric binding sites, the interaction with the normal ligand may be either enhanced or reduced.

Allosteric enzyme
An enzyme that contains a region to which small, regulatory molecules (“effectors”) may bind in addition to and separate from the substrate binding site and thereby affect the catalytic activity. On binding the effector, the catalytic activity of the enzyme towards the substrate may be enhanced, in which case the effector is an activator, or reduced, in which case it is a de-activator or inhibitor.

Allosteric regulation
The regulation of the activity of allosteric enzymes. (See also Allosteric binding sites; Allosteric enzymes).

Analog
In the medicinal chemistry context, it is a drug whose structure is related to that of another drug but whose chemical and biological properties may be quite different. (See also Congener).

Analytical Construct
Tool for the development of chemistry on a solid support whereby the desired compound is prepared in a form which facilitates analysis. This may be achieved by the insertion of an additional orthogonal linker between the solid support and the standard linker, thus allowing release of the linker-bound compound at any desired point in compound assembly. Dual linker systems are currently used to design analytical constructs.

Antagonist
A drug or a compound that opposes the physiological effects of another. At the receptor level, it is a chemical entity that opposes the receptor-associated responses normally induced by another bioactive agent. Antagonist binds to the receptor but does not produce the biological effect. It may oppose the action of an agonist.

Antimetabolite
A structural analog of an intermediate (substrate or coenzyme) in a physiologically occurring metabolic pathway that acts by replacing the natural substrate thus blocking or diverting the biosynthesis of physiologically important substances.

Antisense molecule
An oligonucleotide or analog thereof that is complementary to a segment of RNA (ribonucleic acid) or DNA (deoxyribonucleic acid) and that binds to it and inhibits its normal function.

Aptamer
Oligonucleotide or peptide-based molecules which display specific binding to a protein or other target, often selected by an iterative cycle of affinity-based enrichment (see also SELEX). More specifically, aptamers can be classified as: DNA or RNA aptamers (they consist of (usually short) strands of oligonucleotides) and peptide aptamers (they consist of a short variable peptide domain, attached at both ends to a protein scaffold). Aptamers can be used for both basic research and clinical purposes as macromolecular drugs. They can be combined with ribozymes to self-cleave in the presence of their target molecule.

ArgoGel
(Trademark of Argonaut Technologies, San Carlos, California, USA). Beaded solid support with a crosslinked polystyrene core and grafted linear poly(ethylene glycol) (PEG) chains with terminal functional groups; for example, ArgoGel-Cl, ArgoGel-NH2, ArgoGel-MB-CHO, Wang Resin.

Array Synthesis
Form of parallel synthesis in which the reaction vessels are maintained in a specified spatial distribution, e.g. the wells of a 96-well plate or pins held in a rack.

Assay Equivalent
An aliquot of a library which will allow the library to be screened in a single assay. Particularly applicable to libraries prepared by split/pool procedure, where it pertains to the number of particles required to sample a library. Generally consists of a specified number of library equivalents.

Audit
In clinical trials, an audit is a review of source documentation (medical charts, ECG results, lab reports, etc.) at an investigative site and verifying that information against the case report form (form that captures information from a clinical trials).  Regulatory documents are also reviewed by an audited to verify that an investigative site is conducting a study according to all local and federal rules and regulations.  A CRO can be audited to verify that staff have been adequately trained to monitor a clinical trial and that the CRO is following all of their Standard Operating Procedures.

Autacoid
Biological substance secreted by various cells whose physiological activity is restricted to the vicinity of its release; it is often referred to as local hormone.

Autoreceptor
Present at a nerve ending, is a receptor that regulates, via positive or negative feedback processes (usually this is a negative feedback phenomenon), the synthesis and/or release of its own physiological ligand. In general, it is a presynaptic receptor that influences the release of neurotransmitter from the nerve terminal. The terms autoreceptor and presynaptic receptor are frequently used synonymously (see also Heteroreceptor).


B


Backbone
A scaffold of approximately linear configuration. Thus in the generic structure of a tetrapeptide shown below, the repeating polyamide core structure (everything except for the R groups—see Residue) constitutes the backbone.

Bead
(Normally spherical) particle of solid support.

Biased Library
See Directed Library.

Binary Code
Relationship between a set of tags and their corresponding ligands where building block identity is denoted by the presence or absence of a given tag or set of tags (i.e. the two ‘bits’ 1 and 0). Compare quantitative or Ratio Coding.

Binning
Approach to classifying the diversity of a set of compounds by grouping related members in ‘bins’ on the basis of common physical or structural features. Commonly applied to the analysis of a set for the completeness of coverage of the desired property space.

Bioanalytical
Of or relating to the analytical methods used to determine how a drug behaves in a life form.

Bioassay
A procedure for determining the concentration, purity, and/or biological activity of a substance (e.g., drug, vitamin, hormone, plant growth factor, antibiotic, enzyme) by measuring its effect on an organism, tissue, cell, enzyme or receptor.

Bioavailability
The fraction of drug that is absorbed unchanged and then reaches its site of action or the systemic circulation, following administration by any route.

Bioisostere
A compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. Bioisosteres are used interchangeably without significantly changing the overall biological activity of a drug. Thus, the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. A bioisosleric replacement may be used in ‘fine-tuning’ the structure-activity relationships in a series of drugs. It may be physicochemically or topologically based (see also Isostere).

Bioprecursor prodrug
A prodrug that does not imply the linkage to a carrier group, but results from a molecular modification of the active principle itself. This modification generates a new compound, able to be transformed metabolically or chemically, the resulting compound being the active principle.

Biostatistics
In clinical research, a method of analysis used to determine whether a study drug is different from placebo (sugar pill) or a comparator drug (drug that is currently on the market for that indication).

Blood-brain barrier (BBB)
A metabolically active tissue that facilitates and controls the brain uptake of certain solutes while helping to maintain homeostasis within the central nervous system. The BBB consists of a monolayer of polarized cerebral endothelial cells (CEC) that exhibit various functional and morphological differences in comparison with endothelial cells derived from peripheral organs. CEC possess narrow intercellular tight junctional structures.

Blood-Brain Barrier Permeability
The ability of molecule (for example, drug compound) to penetrate through the BBB. For drugs targeting the CNS, BBB penetration is a necessary attribute unless invasive or carrier-based strategies are being considered. On the other hand, for drugs aimed at other sites of action, BBB permeation would be undesirable as it can produce unwanted side-effects.

Building Block
One of a number of interchangeable reagents which can be used in combinatorial library synthesis, part of the structure of which becomes incorporated into the final product, i.e. its residue. See also Diversity Reagent.


C


Capacity
The amount of material which may be attached to a support. May be greater than loading due to, for example, steric effects at the solid surface.

Carrier-linked prodrug (Carrier prodrug)
A prodrug that contains a temporary linkage of a given active substance with a transient carrier group that produces improved physicochemical or pharmacokinetic properties and that can be easily removed in vivo, usually by a hydrolytic cleavage.

Cascade prodrug
A prodrug for which the cleavage of the carrier group becomes effective only after unmasking an activating group.

Catabolism
Consists of reactions involving endogenous organic substrates to provide chemically available energy (e.g., ATP, energy-yielding pathway) and/or to generate metabolic intermediates used in subsequent anabolic reactions. In general, any destructive process by which complex substances are converted by living cells into simpler compounds; destructive metabolism. The phase of metabolism involved in the energy yielding degradation of nutrient (food) molecules.

Catabolite
A naturally occurring metabolite.

Catabolite Repression Common in bacteria
The decreased expression of catabolic enzymes as brought about by a catabolite such as glucose. For example, glucose is the preferred fuel source for certain bacteria, and when present in the culture medium, it represses the formation of enzymes required for the utilization of other fuel sugars, such as β-galactosidase. Since glucose or other catabolites (other molecules derived from glucose) cause the repression, it is known as catabolite repression.

Central Laboratory
In clinical research, a centralized laboratory is often used in order to decrease variability.  When a central laboratory is used, all subject samples (blood, urine, etc.) will be sent to a main laboratory to be analyzed.  

Chemset
A collection of two or more library members, building blocks or reagents; preferred notation in the Journal of Combinatorial Chemistry and convenient for describing synthetic procedures on pools of compounds. Thus ‘chemset 3{1-3} denotes three members of the library produced by the reaction of reagents 2{1-3} with starting material’.

Cleavage
Process of releasing a compound from a solid support, thereby permitting assay or analysis of the compound by solution-phase methods. Dissolution of the compound following cleavage, rather than the cleavage step itself, may be rate-limiting.

Clinical Project Team
The clinical project team is made of various individuals including a clinical project manager, clinical research associates, a project assistant and oftentimes a director.

Clinical Trial Dossier
A Clinical Trial Dossier is a collection of reports that includes information from the manufacturing of a study drug to the outcomes of pre-clinical and clinical trials.  This information is reviewed by regulatory authorities to determine if a clinical trial in humans can commence.

clinical trials
Clinical trials are conducted to allow safety and efficacy data to be collected for new drugs or devices

Clone (common)
A population of genetically identical cells produced from a common ancestor. Sometimes, “clone” is also used for a number of recombinant DNA (deoxyribonucleic acid) molecules all canying the same inserted sequence.

Clone (a molecule)
To create copies of a given molecule via various methods.

Clone (an organism)
A group of individual organisms (or cells) produced from one individual cell through asexual processes that do not involve the interchange or combination of genetic material. As a result, members of a clone have identical genetic compositions. For example, many plants reproduce asexually (without sex) via a process known as apomixis. Protozoa, bacteria, and some animals (e.g., the anemone Anthopleura elegantissima) can reproduce asexually by binary fission, a process in which a single-celled organism undergoes cell division. The result is two cells with identical genetic composition. When these two identical cells divide, the result is four cells with identical genetic composition. These identical offspring are all members of a clone. The word “clone” may be used either as a noun or a verb. Scientists have cloned some adult mammals via nuclear transfer. In that process, the nucleus of an oocyte is removed and replaced with a nucleus taken from another conventional somatic (adult’s body) cell. That oocyte can then grow up to become a clone of the (adult) animal.

cDNA Clone
A DNA molecule synthesized (made) from an mRNA sequence via sequential use of reverse transcriptase (acting on mRNA) and DNA polymerase.

close out visits
After all patients have completed their last study in a clinical trial and all data has been transferred to the data management department, then an investigative site can be be officially “closed” after a close visit has been conducted.

Cluster
Group of compounds which are related by structural or behavioural properties. Organizing a set of compounds into clusters is often used in assessing the diversity of those compounds, or in developing SAR (structure-activity relationship) models. See also Principal Components Analysis, Binning and Recursive Partitioning.

Codon
The sequence of three consecutive nucleotides that occurs in mRNA which directs the incorporation of a specific amino acid into a protein or represents the starting or termination signals of protein synthesis.

Coenzyme
A dissociable, low-molecular weight, non-proteinaceous organic compound (often nucleotide) participating in enzymatic reactions as acceptor or donor of chemical groups or electrons. The coenzyme contains as part of its structure one of the vitamins. This is why vitamins are so critically important to living organisms. Sometimes the same coenzyme is required by different enzymes involved in the catalysis of different reactions. By analogy, a coenzyme is like a part of a car, such as a tire, which can be identified in and of itself and which can, furthermore, be removed from the car. The car (enzyme), however, must of necessity have the tire in order to carry out its prescribed function. Coenzymes have been classified into two large groups: fat soluble and water soluble. Examples of a few water-soluble vitamins are: thiamin, biotin, folic acid, vitamin C, and vitamin B12. Examples of fat-soluble vitamins are: vitamins A, D, E, and K.

Combichem
See Combinatorial Chemistry.

Combinatorial
1.    of, relating to or involving combinations;
2.    of, or relating to the arrangement of, operation on and selection of discrete elements belonging to finite sets.’ (Webster’s Collegiate Dictionary)

Combinatorial Chemistry
Using a combinatorial process to prepare sets of compounds from sets of building blocks.

Combinatorial Library
A set of compounds prepared by combinatorial chemistry. May consist of a collection of pools or sub-libraries. Its composition may be described by the chemset notation.

co-monitoring
Co-monitoring can occur when a CRA (Clinical Research Associate) needs assistance at an investigative site.  The co-monitor is usually another CRA trained in the study.

compliance
In clinical research, when a patient follows the instructions of their doctor (investigator) and when an investigator follows the clinical study protocol.

Combinatorial synthesis
A process to prepare large sets of organic compounds by combining sets of building blocks.

Comparative Molecular Field Analysis (CoMFA)
A 3D-QSAR method that uses statistical correlation techniques for the analysis of the quantitative relationship between the biological activity of a set of compounds with a specified alignment, and their three-dimensional electronic and steric properties. Other properties such as hydrophobicity and hydrogen bonding can also be incorporated into the analysis. (See also Three-dimensional Quantitative Structure-Activity Relationship [3D-QSAR]).

Computational chemistry
A wide discipline using mathematical, neural-based and/or various statistical methods for the calculation of different molecular properties, prediction of activity, pharmacokinetic profile, toxicity, binding, etc, or for the simulation of molecular behavior.

Computer-assisted drug design (CADD)
Involves all computer-assisted techniques used to discover, design and optimize biologically active compounds with a putative use as drugs.

Congener
A substance literally con-(with) generated or synthesized by essentially the same synthetic chemical reactions and the same procedures. Analogs are substances that are analogous in some respect to the prototype agent in chemical structure. In general, congeners are very similar in their structure. Clearly congeners may be analogs or vice versa but not necessarily. The term congener, while most often a synonym for homologue, has become somewhat more diffuse in meaning so that the terms congener and analog are frequently used interchangeably in the literature.

CRAs
Clinical Research Associates are individuals who are trained to monitor a clinical trial.  They visit the investigative sites and review the medical charts to verify that each subject or patient enrolled in a clinical trial is an appropriate candidate and that the site and patient is following the clinical trial protocol.  They also review the regulatory documents and monitor study drug compliance.  The visits are documented in a study report and provided to the sponsor.

CROs
Contract Research Organizations are companies who are contracted by pharmaceutical or biotech companies to manage, monitor, oversee, etc. a clinical trial.

Crosslinking
Property of a solid support prepared from polymeric materials with interconnected strands. Often results from the inclusion of multifunctional monomers in the polymerization reaction, e.g. divinylbenzene in polystyrene production. In such cases, the degree of crosslinking is often quoted as the proportion of the multifunctional monomer in the reaction mixture. The extent of crosslinking is important for physical properties of the solid support, such as the propensity to swell in different solvents.


D


Data Management
All data required to be captured for analysis in a clinical trial is managed by the data management team.  Data is entered into databases and analyzed for completeness and consistency.

Decode
Use of a surrogate analyte to define the reaction path to which the solid support was exposed, and hence imply the structure of a member of a combinatorial library (see also Encoding), or the reaction sequence for its preparation.

Deconvolute
To render less complex; process of optimizing an activity of interest by fractionating (normally by resynthesis, or by elaborating a partial library) a pool with some level of the desired activity to give a set of smaller pools. Repeating this strategy leads to single members with (ideally) a high level of activity and is termed iterative deconvolution.

Dendrimer
A polymer having a regular branched structure. If suitably functionalized it may be used as a soluble support, in which case the desired, dendrimer-supported, material may be isolated by size-exclusion chromatography. Dendrimers may also be attached to a polymer and used as a solid support, with significantly increased loading over the initial resin.

De novo design
The design of bioactive compounds by incremental construction of a ligand model within a model of the receptor or enzyme active site, the structure of which is known from X-ray or nuclear magnetic resonance (NMR) data.

Descriptor
Numerical representation of a molecular property, including bulk properties (e.g. log P, molecular weight), two-dimensional (2D) features (atom connectivities) or three-dimensional (3D) features (molecular shape).

Distomer
Enantiomer of a chiral compound that is the less potent for a particular action. This definition does not excude the possibility of other effect or side effect of the distomer (See also Eutomer).

Direct Divide
Strategy for the assembly of a combinatorial library related to the pool/split process in which each portion of solid support is divided into the next set of reaction vessels without an intervening pooling step. The resulting library is (like a pool/split library) fully combinatorial, with each particle bearing a single library member, but has a reduced standard deviation between the quantity of each library member.

Directed Library
(Also biased or focused library). Library which uses a limited number of building blocks chosen on the basis of pre-existing information or hypothesis which defines the type of functionalities deemed important to obtain a particular activity. See also Unbiased Library.

Directed Sorting
Technique for organizing a mixture of solid-supported samples by identifying each particle (for instance, on the basis of its shape, marking or by reading a radiofrequency code) and transferring it to an appropriate position in an array. See also Sort and Combine.

Diversity
The ‘unrelatedness’ of a set of, for example, building blocks or members of a combinatorial library, as measured by their properties, such as atom connectivity (structural diversity), physical properties, computational measurements or bioactivity.

Diversity Reagent
One of a set of reagents which introduces diversity into the library products, as opposed to one which results in an identical conversion for each member of the library. Similar to building block but may be useful to distinguish from other (i.e. ‘non-diversity’) reagents.

Docking studies
3D-molecular modeling studies aiming at finding a proper fit between a ligand and its binding site.

Double-blind study
Clinical study of potential and marketed drugs, where neither the investigators nor the subjects know which subjects will be treated with the active principle and which ones will receive a placebo.

Double prodrug (or pro-prodrug)
Biologically inactive molecule which is transformed in vivo in two steps (enzymatically and/or chemically) to the active species.

Drug
Any substance presented for treating, curing or preventing disease in human beings or in animals. A drug may also be used for making a medical diagnosis or for restoring, correcting, or modifying physiological functions (e.g., the contraceptive pill).

Drug disposition
All processes involved in the absorption, distribution metabolism and excretion of drugs in a living organism.

Drug latentiation
Chemical modification of a biologically active compound to form a new compound, which in vivo will liberate the parent compound.

Drug targeting
Strategy aiming at the delivery of a compound to a particular tissue of the body.

DSMB
Data Safety Monitoring Board is utilized when safety of patients is of paramount importance.  The DSMB members are individuals not associated with the CRO or pharmaceutical company conducting the trial.  They are “unblinded” (they know which patients are on study drug and which patients are not) and review adverse events associated with the trial.  The DSMB can stop a study if they believe they believe there is a serious safety issue associated with the study drug.

Dual action drug
Compound which combines two desired different pharmacological actions at a similarly efficacious dose.

Dynamic Library
Collection of compounds in dynamic equilibrium. If the composition of the library is altered, for instance by the presence of a receptor which selectively binds certain library members, then shifting of the equilibrium will lead to an increase in the amount of those components which bind to the target with relatively high affinity.


E


EDC
Electronic Data Capture is used when data is entered directly into a database from an investigative site.  EDC is often done on a secure, web-based system.

Efficacy
Describes the relative intensity with which agonists vary in the response they produce even when they occupy the same number of receptors and with the same affinity. Efficacy is not synonymous to Intrinsic activity. It is the property that enables drugs to produce responses. It is convenient to differentiate the properties of drugs into two groups, those which cause them to associate with the receptors (affinity) and those that produce stimulus (efficacy). This term is often used to characterize the level of maximal responses induced by agonists. In fact, not all agonists of a receptor are capable of inducing identical levels of maximal responses. Maximal response depends on the efficiency of receptor coupling, i.e., from the cascade of events, which, from the binding of the drug to the receptor, leads to the observed biological effect.

Elimination
Process achieving the reduction of of the concentration of a xenobiotic including its metabolism.

Encoding
Strategy for pool/split synthesis whereby a surrogate analyte is associated with each member of a combinatorial library. This is often achieved by the use of tags attached to the particle of solid support on which the library members are assembled. This allows the determination of the reaction history of an individual particle.

Enumeration
Conceptual process for explicitly describing discrete members of a library by elaborating the generic structure together with a specified set of residues.

Enzyme
Macromolecule, usually a protein, that functions as a (bio) catalyst by increasing the reaction rate. It is an organic, protein-based catalyst that is not itself used up in the reaction. It is naturally produced by living cells to catalyze biochemical reactions. Each enzyme is highly specific with regard to the type of chemical reaction that it catalyzes, and to the substances (called substrates) upon which it acts. This specific catalytic activity and its control by other biochemical constituents are of primary importance in the physiological functions of all organisms. Although all enzymes are proteins, they may, and usually do, contain additional nonprotein components called coenzymes that are essential for catalytic activity.

Enzyme induction
Process whereby an (inducible) enzyme is synthesized in response to a specific inducer molecule. The inducer molecule (often a substrate that needs the catalytic activity of the inducible enzyme for its metabolism) combines with a repressor and thereby prevents the blocking of an operator by the repressor leading to the translation of the gene for the enzyme.

Enzyme repression
Mode by which the synthesis of an enzyme is prevented by repressor molecules. In other words, it is the inhibition of enzyme synthesis caused by the availability of the product of that enzyme. On a molecular level a repressor molecule (which could be, e.g., the amino acid arginine) combines with a specific repressor protein that is present in the cell. This repressor molecule/repressor protein complex is then able to bind to a specific region of DNA at the initial end of the gene which is called the operator region. It is in this region where the synthesis of mRNA is initiated. The repressor “roadblock” thus stops the synthesis of mRNA, and therefore the synthesis of the protein is also blocked.

Ethics Committee
A committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects.

Eudismic ratio
Potency of the eutomer relative to that of the distomer.


F


Feasibility assessment
When a CRO assesses feasibility surveys that have been returned by physicians who may or may not conduct a clinical trial.  This feedback and be provided to the pharmaceutical company and changes to a protocol may be required based on this feedback.  Also, enrollment rates/plans may be able to be ascertained from this feedback.

feasibility surveys
A CRO may send out a survey to physicians to determine the number of patients s/he could enroll for a particular study.  Additional information may be gathered in these surveys such as the current standard of care, the type of site (hospital vs private practice), etc.

Fingerprint
Numerical representation of a compound or library which describes in a computationally simple fashion a set of attributes (descriptors), such as atom connectives, 3D-structure or physical properties.

Flow Cytometry
Technique for characterizing or separating particles such as beads or cells, usually on the basis of their relative fluorescence.

Fluidic System
Device for synthesis or screening in which fluids such as reagents or assay buffers may be directed to specified locations by the opening and closing of valves in a stationary network of tubes and wells. See also Robotic System.

Fluorous Synthesis
Approach for solution phase synthesis which takes advantage of the ability of highly fluorinated groups to partition out of aqueous and most organic solutions into a third phase consisting of a fluorinated solvent. The fluorinated side-chain acts as a soluble support for synthesis.

Frontal Affinity Chromatography
Method for screening mixtures of compounds for affinity against an immobilized target.

Fully Combinatorial
Containing, or designed to contain, all possible combinations of building blocks. Pool/split libraries are generally fully combinatorial while parallel synthesis libraries may not be. See also Reagent Efficiency.


G


gap analysis
A tool that helps a company to compare its actual performance with its potential performance

GCP
GCP (Good Clinical Practice) is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials or studies.

Genome
A complete set of chromosomal and extrachromosomal genes of an organism, a cell, an organelle or a virus; the complete DNA (deoxyribonucleic acid) component of an organism.

Generic Structure
The general structural formula of a library, consisting of the scaffold plus an indication of the position of attachment of the various residues.

Genetic Algorithm
Method for library design by evaluating the fit of a parent library to some desired property (e.g. the level of activity in a biological assay or the computationally determined diversity of the compound set) as measured by a fitness function. The design of more optimal daughter libraries is then carried out by a heuristic process with simularities to genetic selection in that it employs replication, mutation, deletions, etc. over a number of generations.


H


Hansch analysis
Investigation of the quantitative relationship between the biological activity of a series of compounds and their physicochemical substituent or global parameters representing hydrophobic, electronic, steric and other effects using multiple regression correlation methodology.

Hapten
A low molecular weight molecule that contains an antigenic determinant but which is not itself antigenic unless combined with an antigenic carrier.

Hard drug
A nonmetabolizable compound, characterized either by high lipid solubility and accumulation in adipose tissues and organelles, or by high water solubility. In the lay press the term “Hard Drug” refers to a powerful drug of abuse such as cocaine or heroin.

High-Throughput Screening (HTS)
Process for rapid assessment of the activity of samples from a combinatorial library or other compound collection, often by running parallel assays in plates of 96 or more wells. A screening rate of 100000 assays per day has been termed ‘Ultra High-Throughput Screening’ (UHTS).

Hit
Library component whose activity exceeds a predefined, statistically relevant threshold.

Hit Explosion
Process of establishing structure-activity relationships around a hit by preparing new libraries or series of analogues using related building blocks and/or scaffolds to those employed in the preparation of that hit.

Hit-to-Lead Optimization (strategy) (H2L)
Usually the follow up of high-throughput screening (HTS). Hit-to-Lead strategy is to assess and improve the Drug Metabolism and Pharmacokinetic properties at an early stages of drug discovery. A particular  goal of the hit-to-lead chemistry effort is to improve potency against the target while minimizing off-target toxicities. This may be accomplished empirically by systematic modification of the chemical structure and/or by structure-based design if crystallographic information is available for the target. Alternate chemical scaffolds are examined that retain key recognition features of the hit but are more drug-like in nature (e.g., constrained systems, peptido-mimetics, etc.). The ultimate goal of hit-to-lead is to identify lead compounds that are unlikely to fail in subsequent preclinical and clinical testing, and to do so while “maximizing the efficient use of drug discovery resources”. H2L involves the integration of medicinal chemistry and ADME/Tox studies, generating focused libraries around the most promising hits and using those compounds for early and rapid generation of structure activity relationship (SAR) data.

Homologue
Compound belonging to a series of compounds differing from each other by a repeating unit, such as a methylene group, a peptide residue, etc.

Hormone
A substance (chemical messenger), occurring in both plants and animals, produced by endocrine glands, released in very low concentration into the bloodstream, and which exerts regulatory effects on specific organs or tissues distant from the site of secretion. It acts to inhibit or excite metabolic activities by binding to receptors on specific cells to deliver its “message.” A hormone’s site of production is distant from the site of biological activity (i.e., where the message is delivered).

Human intestinal absorption (HIA)
One of the most important ADME properties. It is commonly defined as the percent dose of orally administered drug to reach the hepatic portal vein, which drains the gastric, superior mesenteric and inferior mesenteric veins of the GI tract into the liver. The absorption of a drug compound through the human intestinal cell lining is an important property for potential drug candidates. Drug molecules are transported from the gastroenteric tract to the blood circle and permeate the gastroenteric membrane by various mechanisms.

Hydrophilicity
Tendency of a molecule to be solvated by water.

Hydrophobicity
Association of non-polar groups or molecules in an aqueous environment which arises from the tendency of water to exclude non polar molecules (see also Lipophilicity).


I


ICH
International Conference on Harmonization: ICH guidelines have been adopted into law in several countries, but used as guidance for the FDA in the form of GCP

IND
Abbreviation for Investigational New Drug.

Initiation
An initiation visit is conducted after all regulatory documents are received and approved by the sponsor and study drug is shipped to the site.  After the initiation visit, where the responsibilities of the investigator are discussed along with the requirements of the study, a site can begin screening patients to enroll into a trial.

Intrinsic Activity
The maximal stimulatory response induced by a compound in relation to that of a given reference compound (See also Partial agonist). This term has evolved with common usage. It was introduced by Ariens as a proportionality factor between tissue response and receptor occupancy. The numerical value of intrinsic activity could range from unity (for full agonists, i.e., agonist inducing the tissue maximal response) to zero (for antagonists), the fractional values within this range denoting partial agonists. Ariëms’ original definition equates the molecular nature of alpha to maximal response only when response is a linear function of receptor occupancy. This function has been verified. Thus, intrinsic activity, which is a drug and tissue parameter, cannot be used as a characteristic drug parameter for classification of drugs or drug receptors. For this purpose, a proportionality factor derived by null methods, namely, relative efficacy, should be used. Finally, “intrinsic activity” should not be used instead of “intrinsic efficacy”. A “partial agonist” should be termed “agonist with intermediate intrinsic efficacy” in a given tissue.

Inverse Agonist
A compound which acts at the same receptor as that of an agonist, yet produces an opposite effect. Such compounds are frequently called negative antagonists. The identification of agents that reduce receptor constitutive activity provided a degree of symmetry and resulted in the terminology of ‘inverse agonist’ for compounds that selectively enrich or favor an inactive state. Ligands that reduce constitutive receptor signaling, and thus stabilize an inactive receptor conformation, are now termed “inverse agonists”.

Investigator
An investigator for a clinical trial is usually a physician who who holds a current medical license and has been approved by the pharmaceutical company to conduct the clinical trial.

In Situ Scaffold Formation

Process whereby a scaffold is formed during library production which contains residues of at least two building blocks; compare Preformed Scaffold.

IR Thermography
Infrared thermography Screening technique where the heat of reaction of a multitude of samples is simultaneously measured. Has been applied in particular to the screening of libraries of potential catalysts.

Iterative Deconvolution
Multistep application of deconvolution where successively smaller sub-libraries are prepared and tested to identify individual active members of a combinatorial library.


K


Kaiser Test
Analytical method for the determination of primary amines. Particularly useful for resin-bound analysis as the chromophoric product is released into solution allowing quantitation by colorimetry.

Knorr Resin
Amide-releasing, acid-cleavable solid support.


L


Ladder Synthesis
Strategy for library assembly where a portion of compound is capped following incorporation of each building block, such that the final sample comprises a mixture of all possible truncated products. This may be designed such that approximately equimolar quantities of each truncated form are present as an approach to gain maximal diversity, or such that each truncate is present in a small amount relative to the fully elaborated product. In the latter case, analysis of the pattern of products serves to identify the parent and is termed ladder encoding.

Lead Compound
A chemical compound that has obvious pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic profile.

Lead Discovery
A process of identifying active new chemical entities, which by subsequent modification may be transformed into a clinically useful drug.

Lead Generation
The term applied to strategies developed to identify compounds which possess a desired but non-optimized biological activity.

Lead Optimization
The synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic requirements for clinical usefulness.

Libraries from Libraries
Strategy for accelerating library production, whereby an existing library is subjected to a relatively minor modification in order to generate a new library, thus avoiding the majority of chemical development and rehearsal required for a new library.

Library Equivalent
The number of samples which equals the number of compounds in the library. Particularly applied to libraries in which individual beads are encoded, where one library equivalent is the number of beads which equals the number of compounds in the library. See also Assay Equivalent.

Linker
Bifunctional chemical moiety attaching a compound to a solid support or soluble support which can be cleaved to release compounds from the support. A careful choice of linker allows cleaveage to be performed under appropriate conditions compatible with the stability of the compound and assay method.

Liquid Phase Chemistry
Synthetic process employing a macromolecular soluble support.

Lipophilicity
Represents the affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behaviour in a biphasic system, either liquid-liquid (e.g., partition coefficient in octan-1-ol/water) or solid-liquid (retention on reversed-phase high performance liquid chromatography (RP-HPLC) or thin-layer chromatography (TLC) system). See also Hydrophobicity.


M


Macroporous Resin
Polymer which contains a permanent network of pores independent of the state of swelling of the resin. This class of resin thus displays much better solvent tolerance than gel-type resins.

Magic Angle Spinning
NMR strategy in which the tube is rotated at very high speed and at a specific angle which cancels out the line broadening effects of inhomogeneities in the sample. This yields high resolution and high sensitivity which are very useful in trace analysis or in looking at solid phase synthesis resins. This method is available for analyzing compounds on individual beads like FT-infrared spectroscopy.

Medical Monitor
A physician, employed by either the biotech or pharmaceutical company or the CRO, to oversee medical aspects of a clinical trial such as lab and ECG results, adverse events and serious adverse events.

Medicinal Chemistry
A chemistry-based discipline, also involving aspects of biological, medical, computational and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of various QSARs.

Mesh Size
The density of wires in a sieve. Often used as a measure of particle size, for example, of solid supports. A resin whose particle size is quoted as 100-200 mesh will pass through a 100-mesh filter but is trapped by a 200-mesh filter, and consists of particles whose diameter is between 75 and 150 m. There are, unfortunately, several standard scales for this measurement which differ only very slightly from one another.

Metabolism
The term metabolism comprises the entire physical and chemical processes involved in the maintenance and reproduction of life in which nutrients are broken down to generate energy and to give simpler molecules (catabolism) which by themselves may be used to form more complex molecules (anabolism). Conversion of food and water into nutrients that can be used by the body’s cells, and the use of those nutrients by those cells (to sustain life, grow, etc.). In case of heterotrophic organisms, the energy evolving from catabolic processes is made available for use by the organism. In medicinal chemistry the term metabolism refers to the biotransformation of xenobiotics and particularly drugs, (See also Biotransformation; Xenobiotic).

Metabolite
A chemical intermediate in the enzyme-catalyzed chemical reactions of metabolism.

Me-too Drug
A compound that is structurally very similar to already known drugs, with only minor pharmacological differences (also see Generic compound).

Monomer
Member of a building block set which can be repeatedly incorporated into a library to give a set of compounds of repeating structure, e.g. amino acids in a peptide library.

MPS
Multiple parallel synthesis

Mutagen
An agent that causes a permanent heritable change (i.e., a mutation) into the DNA (deoxyribonucleic acid) of an organism. For example, Dr. Gary Shaw discovered in 1996 that women who smoke cigarettes during their pregnancies are twice as likely to have babies with the genetic deformity known as cleft lip and palate. If those women have a particularly susceptible (to smoke) gene variant (allele) within their DNA, they are as much as eight times as likely to have babies with cleft lip and palate. According to the World Health Organization (WHO), 60–80% of all known mutagens are also carcinogens (cancer-causing).

Mutual Prodrug
The association in a unique molecule of two, usually synergistic, drugs attached to each other, one drug being the carrier for the other and vice versa.


N


NDA
Abbreviation for New Drug Application

New Chemical Entity (NCE)
A compound not previously described in the literature.

Neural Networks (Artificial Neural Networks, ANNs)
In general, it is a mathematical model or computational model that tries to simulate the structure and/or functional aspects of biological neural networks. In the medicinal chemistry context, ANNs are regarded as advanced QSAR tools for drug discovery.

Nucleic Acid
A macromolecule (a nucleotide polymer) composed of linear sequences of nucleotides that perform several functions in living cells, e.g., the storage of genetic information and its transfer from one generation to the next DNA (deoxyribonucleic acid), the expression of this information in protein synthesis (mRNA, tRNA) and may act as functional components of subcellular units such as ribosomes (rRNA). RNA (ribonucleic acid) contains D-ribose, DNA contains 2-deoxy-D-ribose as the sugar component. Nucleic acid contain phosphate groups, sugar groups, and purine and pyrimidine bases. The bases involved are adenine, guanine, cytosine, and thymine (uracil in RNA).

Nucleoside
A compound in which a purine or pyrimidine base is bound via a N-atom to C-1 replacing the hydroxy group of either 2-deoxy-D-ribose or of D-ribose, but without any phosphate groups (see also Nucleotide). The common nucleosides in biological systems are adenosine, guanosine, cytidine, and uridine (which contain ribose) and deoxyadenosine, deoxyguanosine, deoxycytidine and thymidine (which contain deoxyribose).

Null Reagent
Concept whereby one of a set of pools is subjected to no reaction at a particular stage of a combinatorial synthesis. It is often necessary to record this as a null event to maintain congruence in computational records of the library.


O


Oligonucleotide
An oligomer resulting from a linear sequences of nucleotides.

Omission Library
Strategy for identifying active library members by the systematic omission of building blocks from mixtures. Observation of reduced activity in a certain pool suggests that the building block which was omitted in that pool contributes to activity.

Oncogene
A normal cellular gene which, when inappropriately expressed or mutated, can transform eukaryotic cells into tumour cells.

Orphan Drug
A drug for the treatment of a rare disease for which reasonable recovery of the sponsoring firm’s research and development expenditure is not expected within a reasonable time. The term is also used to describe substances intended for such uses.

Orthogonality
(a)    Property of protecting groups or linkers allowing removal, modification or cleavage of one such without affecting others; (b) pooling strategy whereby library members are incorporated in more than one pool, and are mixed with a different set of other members in each pool. Thus a hit results in two or more active pools with only one member in common.


P


Parallel Synthesis
Strategy whereby sets of discrete compounds are prepared simultaneously in arrays of physically separate reaction vessels or microcompartments without interchange of intermediates during the assembly process. Contrast Pool/Split.

Partial Agonist
An agonist which is unable to induce maximal activation of a receptor population, regardless of the amount of drug applied.

Partial Library
Partly assembled library, or portion thereof, which is reserved to be completed once initial property relationships have been identified. For instance, part of an intermediate pool may not be treated with the final building block until the optimal residue at the final position is known, thus avoiding the need to prepare that pool from the starting materials.

Partial Release
Cleavage process designed to release a compound from a solid support in discrete portions, e.g. by using orthogonal linkers or by controlled application of cleavage reagent or condition. Photocleavable linkers are a particularly convenient application as cleavage may be controlled by simply turning on or off a lamp. Also Controlled Release, Tiered Release.

Passive Transport
Means moving ions or compounds (for example, drugs or biomolecules, atomic or molecular substances) across the cell membrane. Unlike active transport, this process does not involve chemical energy. The four main kinds of passive transport are diffusion, facilitated diffusion, filtration and osmosis.

Pattern Recognition
The identification of patterns in large data sets using appropriate mathematical methodologies.

Peptidomimetic
A compound containing non-peptidic structural elements that is capable of mimicking or antagonizing the biological action(s) of a natural parent peptide. A peptidomimetic does no longer have classical peptide characteristics such as enzymatically scissille peptidic bonds (see also Peptoid).

Peptoid
A peptidomimetic that results from the oligomeric assembly of N-substituted glycines.

Pfeiffer’s Rule
States that in a series of chiral compounds the eudismic ratio increases with increasing potency of the eutomer.

Pharmacokinetics
Refers to the study of absorption, distribution, metabolism and excretion (ADME) of bioactive compounds in a higher organism.

Pharmacophore (pharmacophoric pattern)
The ensemble of steric, electronic and binding features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure (usually within an active site) and to trigger (or to block) its biological response. A pharmacophore does not represent a real molecule or a real association of functional groups, but a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds towards their target structure. The pharmacophore can be considered as the largest common denominator shared by a set of active molecules. This definition discards a misuse often found in the medicinal chemistry literature which consists of naming as pharmacophores simple chemical functionalities such as guanidines, sulfonamides or dihydroimidazoles (formerly imidazolines), or typical structural skeletons such as flavones, phenothiazines, prostaglandins or steroids.

Phage Display
Use of genetically engineered phage to present peptides as segments of their native surface proteins. Peptide libraries may be produced by populations of phage with different gene sequences.

Phase IV
Phase IV (or Phase 4) clinical trials are also called “post-marketing” studies.  They are trials that are done after a drug has been approved by the FDA and is on the market for that approved indication.

Phase Switch
Strategy for compound isolation, whereby the desired material is rendered sufficiently different from reagents, side-products and other impurities that it may be separated from them by simple physical processes such as filtration or extraction. May be achieved by the attachment of a tag, such as a highly fluroinated component (see Fluorous Synthesis), or other sequestration enabling reagent.

Photolithography
Process by which selective masking generates light patterns which direct chemical transformations to certain areas of a photosensitive surface. Coupling of different building blocks to discrete sites may give rise to spatially addressable arrays of compounds.

P-glycoprotein
A large membrane-bound protein present in the canalicular domain of hepatocytes, brush border of proximal tubule cells and capillary endothelial cells in the central nervous system, which acts as a barrier to limit the exposure to xenobiotics.

Pin
An elongated device in which the tip acts as a solid support. An array of pins may typically be held such that sets of pins may be simultaneously inserted or retracted from solvents or reagents allowing library preparation by parallel synthesis.

Placebo
An inert substance or dosage form which is identical in appearance, flavor and odour to the active substance or dosage form. It is used as a negative control in a bioassay or in a clinical study.

Plasma Protein Binding
The ability of compound (for example, drug) to bind to plasma proteins. These proteins include: human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ globulins. Thus, a drug in blood exists in two forms: bound and unbound, and both forms are responsible for drug activity and efficiency. Plasma proteins are the major vehicle for transport and buffering of drug compounds. The clinical potential of drug compounds is greatly affected by the nature of their interactions with circulating plasma proteins, such as human serum albumin (HSA) and 1-acid glycoprotein (AGP). Plasma protein binding varies greatly and affects the free concentration of the drug in the circulation, as well as transport and distribution in the body, and the duration of drug action.

Point of Diversity
Portion of a molecule, or step in a synthetic scheme, where different building blocks may be introduced.

Poly(ethylene glycol) (PEG)
Polymer which has been applied both as a soluble support and (as a graft copolymer with a polystyrene matrix) as a linker for combinatorial synthesis. See TentaGel, ArgoGel. The soluble support may have hydroxyls at both termini, or one or both may be capped or modified with additional functionality.

Pool
(a)    A sub-library; (b) process of combining and mixing library components or sub-libraries.

Pool/Split
(split/pool; split&mix; divide, couple, recombine; portion/mix) Strategy for assembly of a combinatorial library. The solid support is divided into portions, each of which is subjected to reaction with a single building block. Pooling of these portions results in a single batch of solid support bearing a mixture of components. Repetition of the divide, couple, recombine processes results in a library where each discrete particle of solid support carries a single library member, and the number of members is equal to the product of the number of building blocks incorporated at each step (i.e.. fully combinatorial).

Positional Scan
Strategy for identifying individual compounds of interest from a library, whereby a collection of sub-libraries is prepared, equal in number to the total number of building blocks used in the entire library. In each pool, one point of diversity is held constant by incorporating a single building block, while the other positions use all possible building blocks.

Potency
Dose of drug required to produce a specific effect of given intensity as compared to a standard reference. Potency is a comparative rather than an absolute expression of drug activity. Drug potency depends on both affinity and efficacy. Thus, two agonists can be equipotent, but have different intrinsic efficacies with compensating differences in affinity.

Principal Components Analysis
Computational approach to reducing the complexity of, for example, a set of descriptors, by identifying those features which provide the major contributions to observed properties, and thus reducing dimensionality of the relevant property space.

Preformed Scaffold
A scaffold which is incorporated into the library as a unit. Compare In Situ Scaffold.

Privileged Structure
Substructural feature which confers desirable (often drug-like) properties on compounds containing that feature. Often consists of a semi-rigid scaffold which is able to present multiple hydrophobic residues without undergoing hydrophobic collapse, e.g. diazepam in which the diphenylmethane moiety prevents association of the aromatic rings.


Prodrug
Any compound that undergoes biotransformation before exhibiting its pharmacological effects. Prodrugs can thus be viewed as drugs containing specialized non-toxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule (see also Double prodrug).

Property Space
Multidimensional representation of a set of compounds in which the axes represent quantifiable properties, such as molecular weight, c log P, molar refractivity, etc., and individual compounds are represented by a vector or set of coordinates.


Q


Quantitative Structure-Activity Relationships (QSAR)
Mathematical relationships linking chemical structure and pharmacological activity (or any drug-related property) in a quantitative manner for a series of compounds. Methods which can be used in QSAR include various regression and pattern recognition techniques, artificial neural nets and different statistical tools, 2D- and 3D-computational techniques, including pharmacophore modeling and molecular docking.


R


Radiofrequency Encoding
Strategy for identifying library members by physically associating them with a set of electronic devices which emit characteristic radiofrequency signals upon stimulation with a radiofrequency energy source. These signals can be used to track the reaction history of each sample in a synthesis.

Ratio Coding
Encoding strategy in which the relative quantities of tags conveys information about compound identity. In comparison to binary coding, more information may be obtained from a given tag set, but tag interpretation is more complex.

Reagent Efficiency
The ratio of the number of library members prepared compared to the number which would have been prepared in a fully combinatorial library using the same building blocks. Lower reagent efficiency may be desirable in order to reduce the number of compounds to be synthesized or tested, for example by maximizing the number of members expected to have high activity in a library prepared by parallel synthesis.

Reagent Partitioning
Phenomenon whereby the concentration of a compound within, for instance, a particle of solid support is higher or lower than than of the bulk solution due to the physicochemical properties of the solid support.

Receptor
Molecule or a polymeric structure in or on a cell that specifically recognizes and binds a compound acting as a molecular messenger (neurotransmitter, hormone, lymphokine, lectin, drug, etc.).

Receptor Mapping
Technique used to describe the geometric and/or electronic features of a binding site when insufficient structural data for this receptor or enzyme are available. Generally the active site cavity is defined by comparing the superposition of active to that of inactive molecules.

Recruitment Estimates
Recruitment estimates are based on a qualified assumption of how many patients can be enrolled in a study within a certain timeframe.  These estimates are often used to project out the length and cost of a clinical trial.  For example, enolling 1 patient per site per month is a recruitment estimate.

Recursive Partitioning
Process for identifying complex structure-activity relationships in large sets by dividing compounds into a hierarchy of smaller and more homogeneous sub-groups on the basis of the statistically most significant descriptors.

Regulatory Approval
Before any clinical trial begins, the study protocol and all safety information must be reviewed and approved by the regulatory authority of the country as well as local ethics committees or institutional review boards.  

Regulatory Authorities
A committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects.

Residue
(a)    Portion of a chemical structure which can be identified as being derived from a particular building block, such as alanine residue in a peptide molecule; (b) portion of a building block which is incorporated into the final product but is not part of the scaffold.

Resin
Insoluble polymeric material which allows ready separation from liquid phase materials by filtration; can be used to carry library members (i.e. solid support) or reagents, or to trap excess reagents or reaction by-products (see Scavenger Resin).

Re-synthesis
Preparation of individual members or pools of a combinatorial library, normally to follow up on some property of interest identified in initial screening, and often in larger scale and/or greater purity than the original preparation.

Rink Resin
Amide-releasing, acid-cleavable solid support. 4-(2′,4′-Dimethoxyphenylaminomethyl)-phenoxy polystyrene.

Robotic System
Automated device where materials are transferred by the physical movement of a delivery device relative to the ultimate receptacle, or vice versa.

Rules of Five
Lipinski’s rules. Set of criteria for predicting the oral bioavailability of a compound on the basis of simple molecular features (molecular weight, c Log P, numbers of hydrogen-bond donors and acceptors). Often used to profile a library or virtual library with respect to the proportion of drug-like members which it contains.


S


SAE
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: 1) results in death; 2) is life threatening; 3) requires inpatient hospitalization or prolongation of existing hospitalization; 4) results in persistent or significant disability/incapacity, or 5) is a congenital anomaly/birth defect.

Safety-Catch Linker
A linker which is cleaved by performing two different reactions instead of the normal single step, thus providing greater control over the timing of compound release. For example, a sulfonamide resin must first be alkylated to render it susceptible to cleavage by nucleophilic displacement.

Safety Surveillance
A physician, employed by either the biotech or pharmaceutical company or the CRO along with a team of drug safety associates, will review adverse events and serious adverse events, ECG results and laboratory reports to verify appropriate follow up by the investigators as well as to look for concerning trends that would affect patient safety.

Scaffold
Core portion of a molecule common to all members of a combinatorial library.

Scavenger Resin
Solid-supported reagent which will react with undesired materials (such as excess reagents) and remove them from solution. See also Sequestration-Enabling Reagent.

Second Messenger
Molecule (for example, cAMP) or ion inside cells that acts to transmit signals from a receptor to a target. The term second messenger was coined upon the discovery of these substances in order to distinguish them from hormones and other molecules that function outside the cell as “first messengers” in the transmission of biological information. Many second messenger molecules are small and therefore diffuse rapidly through the cytoplasm, enabling information to move quickly throughout the cell. As elements of signaling pathways, second messengers can serve to integrate information when multiple independent upstream inputs influence the rates of synthesis and degradation of the second messenger. G Protein-Ccoupled Receptors (GPCRs) are the most representative within this group.

SELEX
“Systematic Evolution of Ligands by Exponential Enrichment”. Process for identifying aptamers by iterative enrichment of oligonucleotide mixtures with respect to their ability to bind a target.

Sequestration-Enabling Reagent
Reagent which converts undesired by-products or residual starting materials into a form which may more easily be removed from the reaction mixture by, for example, solid phase extraction or other phase switch.

Site-specific delivery
Approach to target a drug to a specific tissue, using prodrugs or antibody recognition systems.

Site Isolation
Property of solid supports, whereby functional groups are separated from each other by the polymeric framework, and thus, while they may be physically in close promimity, reduced levels of reaction between sites may be observed. Also referred to as pseudo-dilution.

Soft drug
A compound that is degraded in vivo to predictable non-toxic and inactive metabolites, after having achieved its therapeutic role.

Solid Phase Extraction
Method for sample purification, whereby either the desired or undesired components of a mixture have preferential affinity for a solid material. Adding the mixture to the solid material then allows facile separation of the desired material by nitration. See also Sequestration-Enabling Reagent and Scavenger Resin.

Solid Support
Insoluble, functionalized, polymeric material to which library members or reagents may be attached (often via a linker) allowing them to be readily separated (by filtration, centrifugation, etc.) from excess reagents, soluble reaction by-products or solvents.

Soluble Support
An attachment, common to all library members, which renders the library components soluble under conditions for library synthesis, but which can be readily separated from most other soluble components when desired by some simple physical process. This process has been termed liquid phase chemistry. Examples of soluble supports include linear polymers such as poly(ethylene glycol), dendrimers or fiuorinated compounds which selectively partition into fluorine-rich solvents (see Fluorous Synthesis).

SOP
Standard Operating Procedures (SOPs) detail the regularly recurring work processes that are to be conducted or followed within an organization. They document the way activities are to be performed to facilitate consistent conformance to technical and quality system requirements and to support data quality.  For clinical trials, SOPs are often based on GCP (Good Clinical Practice).

Sort and Combine
Use of directed sorting to facilitate library assembly. Related to pool/split protocol, but more commonly applied to macroscopic solid supports (such as pins and related carriers) where each library member is found on only one, or a small number of carriers.

Spatially Addressable
Having the ability to identify at least part of the structure of a library component or pool by noting its physical location in an array.

“Split- and- combine” Procedure
Permits the synthesis of a multitude of individual compounds to be carried out on bead particles, each of which has only one defined compound attached to it, albeit in multiple copies, has had a major impact on combinatorial chemistry. This approach minimizes the synthetic effort per compound, as compounds can be screened as mixtures either while they remain attached to the solid support, or after being released from the bead into solution. The split- and- combine approach is ideal for the synthesis of minute amounts of a plethora of compounds, but it has one disadvantage in that it is boun associated with a rather time-consuming deconvolution process that involves iterative rounds of resynthesis and screening of compound subsets in order to identify the active compound. The danger exists that the originally identified activity is the sum of several moderate activities, so that invariably the original activity is lost during the deconvolution process.

Stochastic
‘Aiming, proceeding by guesswork’. (Websters Collegiate Dictionary.) Term which is often applied to combinatorial processes involving true random sampling, such as selection of beads from an encoded library, or certain methods for library design.

Structure-activity Relationship (SAR)
Relationship between chemical structure and pharmacological activity for a series of compounds.

Structure-based Design
A drug design strategy based on the 3D-structure of the target obtained by X-ray or NMR.

Structure-Property Correlations
All statistical mathematical methods used to correlate any structural property to any other property (intrinsic, chemical or biological), using various computational techniques.

Sub-Library
A subset of a combinatorial library, physically separate from the rest of the library, generally with one or more fixed building blocks.

Sub-Monomer Synthesis
Process resulting in an oligomer in which each monomer residue is formed from two or more building blocks. This approach has been used for peptoid synthesis.

SURF
‘Synthetic Unrandomization of Randomized Fragments’ Strategy for identifying active members of a mixture related to deconvolution and positional scanning.


T


Tag
(a)    One of a set of surrogate analytes which are used in a decoding process; (b) pendant function which allows a molecule to be selected from a mixture (see Phase Switch).

Tea-Bag
A type of reaction vessel consisting of a porous mesh which encloses the resin but allows passage of reagents and solvents when immersed in an appropriate secondary container. Several tea-bags may be treated in a single vessel without mixing of the enclosed resins; manipulation of multiple tea-bags allows preparation of libraries by pool/split or directed sorting techniques.

TentaGel
(Trademark of Rapp Polymere GmbH, Tubingen, Germany.) Beaded solid support with a crosslinked polystyrene core and grafted linear poly(ethylene glycol) (PEG) chains with terminal functional groups.

Teratogen
Substance that produces a malformation in a foetus.

Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR)
Analysis of the quantitative relationship between the biological activity of a set of compounds and their spatial properties using 3D computational tools, such as molecular docking and pharmacophore modeling.

Topliss Tree
Operational scheme for analog design.

Traceless Linker
Type of linker which leaves no residue on the compound after cleavage, i.e. is replaced by hydrogen, for example germanium-based linker.

Transition-state Analog
Compound that mimics the transition state of a substrate bound to an enzyme.


U


Unbiased Library
Library prepared from building blocks and scaffold chosen without bias towards a particular target.

Universal Library
A hypothetical compound collection which will show activity in all assays; a library with useful activity in many assays.


V


Virtual Library
Library which has no physical existence, being constructed solely in electronic form or on paper. The building blocks required for such a library may not exist, and the chemical steps for such a library may not have been tested. These libraries are used in the design and evaluation of possible libraries.

Virtual Screening
Computational technique widely used in drug design & discovery. It involves the `rapid` in silico assessment of large libraries of chemical structures in order to identify those structures that most likely to bind to a drug target (e.g. receptor, protein or enzyme) producing the desired therapeutic response. Also termed in silico screening.


W


Wang Resin
Acid-cleavable resin which generates compounds bearing a carboxylic acid. (4-Hydroxymethyl)phenoxymethyl polystyrene.


X


Xenobiotic
Compound foreign to an organism (xenos [greek] = foreign).

X-Ray Photoelectron Spectroscopy (XPS)
Technique for determining the elemental composition at a solid surface by measuring the energy of electrons emitted in response to X-rays of different frequency. Has been applied to solid phase combinatorial chemistry by incorporating a tracer atom in the linker.