Mechanistic Insights into Nitrile and Alkyne Covalent Inhibitors of the SARS-CoV-2 Main Protease.

ABSTRACT: The treatment of SARS-CoV-2 can be accomplished by effective suppression of its 3CL protease (3CL^pro), also known as the main protease (M^pro) and nonstructural protein 5 (nsp5). Covalent inhibitors can irreversibly and selectively disable the protease, particularly when they are highly exothermic. Herein we investigated the distinct kinetic behaviors exhibited by two covalently linked SARS-CoV-2 inhibitors. One of these inhibitors features a nitrile reactive group, while the other has this group replaced by an alkyne group, a less reactive electrophile. Our investigations involve the assessment of the free energy surfaces of the key feasible mechanisms: that is, direct and water-assisted mechanisms involved in the rate-determining proton-transfer nucleophilic attack s

SUBMITTER: Nandi A 

PROVIDER: S-EPMC12419483 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature