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PPI Helix Turn 3D-Mimetics Library

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  • Mg
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ChemDiv’s library of small molecule compounds engaging with protein-protein interactions via 3d-mimicking helix turns contains 68,388 entries.


Protein-protein interactions (PPIs) have become the predominant target class in high-throughput screening (HTS) studies. Despite this, the success rate of identifying active and efficacious compounds through various HTS campaigns leveraging small molecule compounds remains notably low. This trend emphasizes a critical challenge: most conventional chemical libraries are not fit for effective targeting of PPIs. To address this issue, there is a pressing need for the deliberate design of PPI-focused libraries that can cover a large chemical space conducive to interacting with these complex targets. In comparison to the majority of traditional drugs, presently known PPI inhibitors exhibit distinctive characteristics—they tend to be larger, more hydrophobic, and feature a higher prevalence of (hetero)aromatic rings, positioning them within the "beyond Rule of 5" (bRo5) chemical domain.

The industry has increasingly recognized the value of compounds that exhibit diverse and well-defined three-dimensional shapes, marking a significant shift toward the preference for screening compounds in HTS studies over recent years. The Fsp3 parameter, introduced by Frank Lovering et al. in 2009 [1], has emerged as a critical metric for evaluating the value of HTS libraries. This parameter measures the three-dimensionality and complexity of the compound library entries. Analysis based on this metric, alongside further observations, suggests that scaffold or molecule saturation confers numerous advantages, including:

-       Enhanced diversity and complexity, facilitating access to a broader chemical space.

-       Improved physicochemical parameters, such as logP, polar surface area (PSA), and water solubility.

-       Opportunities to reduce the molecular weight of the scaffold, thus enhancing drug-like properties.

-       Flexibility for further modifications of the scaffold, enabling the exploration of novel chemical entities.

-       A greater resemblance to natural compounds, which often exhibit high degrees of complexity and three-dimensionality.

-       Increased affinity and selectivity towards target proteins, which were shown to be critical for the efficacy and safety of potential therapeutics.

-       Facilitated entry into intellectual property (IP)-clean areas, essential for the commercial viability of new drugs.

These insights underscore the necessity of adopting innovative approaches in the design and utilization of HTS libraries, particularly those aimed at the challenging yet therapeutically promising realm of PPIs. Prioritizing compounds with sophisticated three-dimensional structures and optimizing for parameters like Fsp3, can significantly enhance the prospects of discovering viable PPI inhibitors, thereby advancing the frontier of drug discovery in addressing complex diseases.

Those findings led to the development of a new library subset within our PPI-focused library, specifically the Helix/Turn 3D-Mimetics Library. This specialized library has been meticulously designed using sp^3-enriched scaffolds derived from our diversity-oriented synthesis (DOS) chemistry. It is populated with the molecules capable of emulating α-helices and β-turns, which are crucial recognition elements in protein secondary structures.

For the selection of preferred scaffolds, we adhered to the following criteria:

-       sp^3-enrichment (Fsp3 ≥ 0.4) that ensures scaffold complexity and, consequently, three-dimensional diversity, which is vital for mimicking the intricate nature of protein structures.

-       Diversification points suggest that scaffolds must contain at least two, but preferably more, points of diversification. This allows for the introduction of structural elements that can act as recognition units, such as side chains mimicking those of proteinogenic amino acids with a high helix propensity. Examples include iso-propyl, iso-butyl, benzyl, carboxyl, aminoalkyl, hydroxyalkyl, carboxamide groups, and aromatic heterocycles like imidazole and indole.

-       Privileged structure moieties, or "privileged structures," are essential in the library. Such structures, which have shown a high degree of utility in medicinal chemistry, include piperazines, piperidines (with specific functionalities such as 3- or 4-amines, carboxamides), pyrrolidines, benzodiazepines, unusual prolines, and others.

-       Natural compound motifs moieties from naturally occurring compounds should be incorporated to exploit the biological relevance and inherent bioactivity of these structures.

-       Lipophilicity/Hydrophilicity Balance is crucial to maintaining balanced lipophilicity and hydrophilicity to ensure optimal bioavailability and membrane permeability.

-       The use of conformationally constrained systems, such as spiro- and bridged heterocyclic systems, is favored to enhance the specificity of interaction with target proteins by mimicking the rigid structures found in natural protein-ligand interactions.

By meeting these stringent criteria, the Helix/Turn 3D-Mimetics Library is poised to offer a rich source of compounds for the discovery of novel inhibitors targeting protein-protein interactions. These compounds are specifically designed to interact with and disrupt the complex networks of protein interactions, paving the way for the development of innovative therapeutic agents.


[1] Lovering, F., Bikker, J., Humblet, C. Escape from flatland: Increasing saturation as an approach to improving clinical success. J. Med. Chem. (2009) 52, 6752–6756 .


1. Hamon V et al. 2014 2P2IHUNTER: a tool for filtering orthosteric protein–protein interaction modulators via a
dedicated support vector machine. J. R. Soc. Interface 11: 20130860. http://dx.doi.org/10.1098/rsif.2013.0860
2. Barker, A., Kettle, J.G., Nowak, T., Pease, J.E. 2013 Expanding medicinal chemistry space. Drug Discov. Today 18, 298–304. (doi:10.1016/j.drudis. 2012.10.008)
3. Fry D et al. 2013 Design of libraries targeting protein–protein interfaces. ChemMedChem 8, 726–732 (doi:10.1002/cmdc.201200540).
4. Morelli, X., Bourgeas, R.; Roche, P. Curr. Opin. Chem. Biol., 2011, 15, 475–481.
5. Bourgeas R, Basse M-J, Morelli X, Roche P. 2010 Atomic analysis of protein–protein interfaces with known inhibitors: the 2P2I database. PLoS ONE 5, e9598. (doi:10.1371/journal.pone.0009598) 24.
6. Hamon, V., Brunel, J. M., Combes, S., Basse, M. J., Roche, P., Morelli X. 2P2Ichem: focused chemical libraries dedicated to orthosteric modulation of protein–protein interactions. Med. Chem. Commun., 2013, 4, 797-809 (DOI: 10.1039/C3MD00018D)
7. Laraia, L.; Spring, D. R. Chemical library screening approaches to aid the design of protein–protein inhibitors, Pages 32-45 (doi: 10.4155/ebo.13.151) In: Understanding and Exploiting Protein–Protein Interactions as Drug Targets 151 pages October, 2013, Future Science Ltd (doi: 10.4155/9781909453463)
8. Zhang, , X, Betzi, S., Morelli, X., Roche, P. Focused chemical libraries – design and enrichment: an example of protein–protein interaction chemical space. Future Med. Chem. (2014) 6(11), 1291–1307. (doi:10.4155/fmc.14.57).
9. Milroy, L.-G. et al. Modulators of Protein−Protein Interactions. Chem. Rev. 2014, 114, 4695−4748 (dx.doi.org/10.1021/cr400698c)
10. Rizzo, S.; Waldmann, H. Development of a Natural-Product-Derived Chemical Toolbox for Modulation of Protein Function. Chem. Rev. 2014, 114, 4621-4639 (DOI: 10.1021/cr400442v).
11. Hajduk, P.J., Galloway, W.R.J.D., Spring, D.R. Drug discovery: A question of library design. Nature 470, 42–43 (2011).
12. Hung, A.W. et al. Route to three-dimensional fragments using diversity-oriented synthesis. Proc. Natl. Acad. Sci. USA. 108, 6799-6804 (2011).
13. Lovering, F., Bikker, J., Humblet, C. Escape from flatland: Increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).
14. Bourne, G.T.; Kuster, D.J.; Marshall, G.R. Synthesis of the Phenylpyridal Scaffold as a Helical Peptide Mimetic. Eur. J. Chem, 2010, 16(28), 8439-8445.
15. Witby, L.R. ; Boger, D.L. Comprehensive Peptidomimetic Libraries Targeting Protein_Protein Interactions. Acc. Chem. Res. 2012, 45, 1698 – 1709.

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