Alfa Chemistry is an expert in the field of drug discovery and has established an advanced DNA-encoded libraries (DELs) technology platform dedicated to building and synthesizing a large number of novel, diverse, drug-like compound libraries.
Our world-class laboratories and scientists can support your unique synthetic needs and help you apply covalent DELs to enable affinity screening against targeted proteins for hit discovery.
Introduction to Covalent Drugs
Covalent drugs contain a mildly reactive functional group that forms a covalent bond with the protein target, providing additional affinity in addition to the non-covalent interactions involved in drug binding. Over the past two decades, interest in covalent drugs has increased significantly, and more and more covalent drugs have been developed, as shown in Fig. 1 [1].
Covalent inhibitors, as covalent drugs, also known as irreversible inhibitors, are a type of small organic molecules that can interact with specific target proteins and form covalent bonds, causing changes in protein conformation and thereby inhibiting protein activity. One key advantage of covalent inhibitors is their potential for enhanced selectivity and specificity. In addition, unlike reversible inhibitors, which bind transiently to their targets, covalent inhibitors form a durable linkage, often leading to prolonged inhibition and enhanced potency. This mechanism allows for precise modulation of specific protein targets implicated in disease pathways, offering potential therapeutic benefits across various medical conditions [2].
Fig. 1 Timeline of the development of major covalent drugs [2].
Our Capabilities
Leveraging the advanced DELs technology platform, Alfa Chemistry specializes in designing and synthesizing covalent DELs tailored to discovering covalent inhibitors targeting specific proteins of interest. Furthermore, we offer screening condition optimization and compound characterization services tailored specifically for covalent DELs. By combining our expertise in DELs technology with the utilization of covalent libraries, we provide researchers with comprehensive and innovative tools for advancing drug discovery efforts.
Structure of covalent DELs: The structure of a covalent inhibitor in DELs typically consists of two main parts. The first part serves as a DNA-encoded expandable intermediate, acting as the "guidance system" responsible for determining the inhibitor's selectivity towards the target protein. The second part comprises the reactive group or "warhead," which forms the covalent bond with the target protein. These two parts are combined through a mild DNA/electrophilic group-compatible chemical reaction, resulting in the formation of a complete covalent DELs.
- Alfa Chemistry boasts molecular building blocks with a diverse array of unique skeletons, serving as scalable intermediates. These building blocks are derived from a multitude of chemical combinations to ensure sufficient novelty, diversity, and drug-like properties.
- Alfa Chemistry offers a wide range of electrophilic groups, serving as covalent "warheads" with distinct structures and mechanisms. Our "warheads" include commonly used cysteine residues, α,β-unsaturated ketones, and Michael acceptors, targeting different proteins.
- Alfa Chemistry can construct tailored covalent inhibitor libraries by leveraging the binding ability of covalent "warheads" to active amino acid residues. Beyond offering covalent DELs designed explicitly for cysteine, our services extend to providing DELs for other critical amino acid residues like lysine and serine.
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References
- Boike, L.; et al. Advances in covalent drug discovery. Nature Reviews Drug Discovery. 2022, 21: 881–898.
- Li, L.; et al. Triazine-based covalent DNA-encoded libraries for discovery of covalent inhibitors of target proteins. ACS Med. Chem. Lett. 2022, 13(10): 1574–1581.