Covalent inhibitors Library

The R&D of non-covalent inhibitors has been a primary focus in drug discovery. Despite their relatively weaker binding affinity to targets, researchers have consistently tried to enhance drug effects through structural optimization and dose adjustments. On the other hand, covalent inhibitors, due to their higher toxicity risks and unclear mechanisms of action, have been largely overlooked. In recent years, with increasing instances of resistance and suboptimal efficacy observed in many non-covalent binding drugs, especially in the case of anti-cancer medications, more attention has been paid to covalent inhibitors.

Compared to non-covalent inhibitors, covalent inhibitors show stronger selectivity, prolonged duration of action, lower effective concentrations, and reduced resistance. A portion of covalent inhibitors has been serendipitously discovered, with compounds like aspirin, penicillin, and fluorouracil playing pivotal roles in the history of drug development. However, in addition to serendipity, the rational design and screening of covalent inhibitors will bring more effective drugs.

Covalent inhibitor molecules consist of two main parts: the guiding head and the warhead. The guiding head initially forms non-covalent interactions with the binding site of the target protein, followed by the warhead covalently binding to the nucleophilic amino acid residue of the target.

Common warheads include Michael acceptors, sulfonyl fluorides, disulfide bonds, α-cyanoacrylamides, and ketone carbonyls. Using existing structures as guiding heads and incorporating appropriate warheads allows the development of covalent inhibitors. This approach facilitates the exploration of new structures and further enhance the selectivity of covalent inhibitors.

The Covalent Inhibitors Library aims to cover common warheads used for covalent reactions, such as chloroacetamide, 2-chloroacetyl, acryloyl, 1-prop-2-ynyl, 1-but-2-ynyl, etc. Additionally, a diversity of unique structures are chosen as guiding heads from the in-stock building block compounds. Various types of covalent inhibitors are designed and synthesized using these building blocks. TargetMol’s Covalent Inhibitors Library currently comprises approximately 12,000 compounds, organized into three sub-libraries: Covalent Inhibitor General Library (approximately 9,000 compounds), Covalent Inhibitor Smart Library (approximately 2,000 compounds), and sp3-enrichedβ-lactam Library (approximately 1,900 compounds), with the numbers continuously increasing. The Covalent Inhibitor General Library includes a wide range of common covalent functional group compounds; the Covalent Inhibitor Smart Library is designed and synthesized by connecting guiding heads and warheads. The sp3-enrichedβ-lactam Library is designed with the core structure of β-lactam.