Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding

Abstract

Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2-S4 binding pockets leading to the first sub-micromolar non-covalent 3CLpro inhibitors retaining a single amide bond.

Rapid Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease by Deep Docking of 1.3 Billion Compounds

“…To assess the performance of fast Glide SP protocol [36] to virtually screen against the Mpro target, we collected 81 known SARS Mpro small molecule inhibitors that are reported by Pillaiyar et al, [37] and Turlington et al. [38] Then, we generated 50 molecular decoys for each active molecules using the methodology implemented in the Database of Useful Decoys: Enhanced (DUDÀ E). [39] All compounds were prepared for docking with the OpenEye package.…”

Recent discovery and development of inhibitors targeting coronaviruses

“…The screening of peptidomimetics (57-60; see Fig. 9) which contains a Michael acceptor group, (i.e., a,b-unsaturated carbonyl) showed moderate anti-CoV activities [107][108][109]. Enterovirus inhibitors 61, 62, and 63, were recently shown to inhibit MERS-CoV with EC 50 values ranging from 1.7 to 4.7 mM [110].…”

Application of heterocyclic aldehydes as components in Ugi–Smiles couplings

“…While such thienyl-substituted aldehydes have been employed in standard Ugi reactions for the preparation of druglike heterocycles [26–28], N -arylamides 4a,b represent the first examples of analogous Ugi–Smiles adducts incorporating a thienyl-substituted aldehyde component.…”