QM/QM studies for Michael reaction in coronavirus main protease (3CL Pro)

Abstract

Severe acute respiratory syndrome (SARS) is an illness caused by a novel corona virus wherein the main proteinase called 3CL Pro has been established as a target for drug design. The mechanism of action involves nucleophilic attack by Cys145 present in the active site on the carbonyl carbon of the scissile amide bond of the substrate and the intermediate product is stabilized by hydrogen bonds with the residues of the oxyanion hole. Based on the X-ray structure of 3CL Pro co-crystallized with a trans-α,β-unsaturated ethyl ester (Michael acceptor), a set of QM/QM and QM/MM calculations were performed, yielding three models with increasingly higher the number of atoms. A previous validation step was performed using classical theoretical calculation and PROCHECK software. The Michael reaction studies show an exothermic process with −4.5 kcal/mol. During the reaction pathway, an intermediate is formed by hydrogen and water molecule migration from a histidine residue and solvent, respectively. In addition, similar with experimental results, the complex between N3 and 3CL Pro is 578 kcal/mol more stable than N1-3CL Pro using Own N-layer Integrated molecular Orbital molecular Mechanics (ONIOM) approach. We suggest 3CL Pro inhibitors need small polar groups to decrease the energy barrier for alkylation reaction. These results can be useful for the development of new compounds against SARS.