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Covalent serine binders library

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Desirable size of the custom library selection:
  • Mg
  • uMol

ChemDiv’s library of serine covalent binders or inhibitors contains 10 chemically diverse warhead scaffolds and counts 4,400 compounds.

Emerging groups of small molecule compounds that covalently bind to serine residues in target proteins offer a unique and potent mechanism for therapeutic intervention. Serine is a nucleophilic amino acid commonly present in the active sites of many enzymes, including proteases, phosphatases, and kinases, which are critical modulators in various biological pathways. By forming covalent bonds with the serine residues, those compounds can irreversibly inhibit activity of such enzymes, leading to sustained effects even after the inhibitor has cleared from the system. This feature is particularly beneficial in treating diseases where constant regulation of enzyme activity is necessary to maintain physiological balance.

The therapeutic utility of serine covalent binders is exemplified in their use against conditions such as diabetes, where the inhibition of DPP-4 (a serine protease) helps in prolonging the action of incretin hormones, thus enhancing insulin secretion and lowering blood glucose levels. Similarly, in the context of infectious diseases, covalent inhibitors of serine proteases in viruses (like the coronavirus main protease) prevent viral replication by blocking the proteolytic cleavage of viral polyproteins, which is essential for virus maturation and infectivity. Moreover, the covalent mechanism ensures that the inhibitors are less susceptible to resistance mutations, a common drawback with reversible inhibitors, as the target enzyme must undergo significant structural changes to overcome the inhibition. This makes serine covalent binders highly effective and provides a durable response, reducing the frequency of dosing and potentially diminishing side effects associated with higher doses or repeated administration.

Serine covalent binders offer significant advantages over non-covalent inhibitors in terms of selectivity, efficacy, and toxicity risk. Covalent binders form irreversible bonds with the serine residue in the active site of target enzymes, which confers a high degree of selectivity and reduces off-target interactions that can lead to side effects and toxicity. This irreversible bonding mechanism not only ensures prolonged inhibition of target enzymes but also enhances the overall efficacy of the drug, as the enzyme remains inhibited for the duration of its lifecycle and cannot readily revert to its active form. Consequently, lower doses of covalent binders can achieve therapeutic effects comparable to higher doses of non-covalent inhibitors, further minimizing the potential for toxicity. Additionally, the precise targeting reduces the likelihood of developing drug resistance, a common issue with non-covalent inhibitors, particularly in fast-evolving diseases such as infectious diseases and cancer, thereby sustaining the drug's effectiveness over longer treatment periods.

Our library of small molecule serine covalent inhibitors provides a robust toolset for discovering and developing novel therapeutics with enhanced specificity and potency. These molecules ensure sustained inhibition, which can lead to improved therapeutic outcomes by maintaining consistent drug activity over extended periods. Such mechanism of action minimizes the required dosage and frequency of administration, potentially reducing side effects and improving patient compliance. Furthermore, the irreversible nature of these covalent interactions significantly curtails the development of resistance, making these molecules particularly valuable in treating conditions where rapid mutation rates diminish the efficacy of non-covalent inhibitors.

The unique development workflow of this library comprises the following stages:

SMARTS Query Preparation: Initial steps that involved preparing a set of SMARTS queries designed to identify literature-derived warheads with specificity towards serine binding. 10 SMARTS patterns were elaborated for the current library.

REOS Filtering: The whole 1.6 million compound inventory made by ChemDiv was subjected to REOS filtering, thus eliminating structurally unfavorable motifs.

Warhead Pattern Matching: The filtered inventory was scanned to identify structures that match predefined warhead SMARTS patterns.

Diversity Selection (MaxMin Algorithm): Within each set of compounds sharing a common warhead scaffold, a diversity-picking approach was employed. The selection criteria include:

a. ensuring an internal set similarity no greater than 0.4 (Tanimoto coefficient and ECFP4 fingerprint with 2048 bits).

The most diverse structures were prioritized for retention, and similar structures were considered for ordering, facilitating the establishment of SAR for promising hits.

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