Inhibitor Design for SARS Coronavirus Main Protease Based on “Distorted Key Theory”

Qi-Shi      Du; Hao      Sun; Kuo-Chen      Chou

Abstract

In order to find effective peptide inhibitors against SARS CoV Mpro, an analysis was performed for 11 oligopeptides that can be cleaved by the SARS coronavirus main protease (CoV Mpro, or 3CLpro). Flexible molecular alignments of the 11 cleavable peptides have provided useful insights into the chemical properties of their amino acid residues close to the cleavage site. Moreover, it was found through the ligand-receptor docking studies that of the 11 cleavable peptides, NH2-ATLQ↓AIAS-COOH and NH2-ATLQ↓AENV-COOH had the highest affinity with SARS CoV Mpro. The two octapeptides were selected as initial templates for further chemical modification to make them become effective inhibitors against the SARS enzyme according to the “distorted key” theory [K. C. Chou, Analytical Biochemistry 233 (1996) 1-14]. The possible chemical modification methods are proposed and examined. The approach developed in this study and the findings thus obtained might stimulate new strategies and provide useful information for drug design against SARS.

Keywords: SARS, CoV Mpro, protease inhibitor, cleavable peptides, rack mechanism, Chou's distorted key theory, bioinformatics