Virtual screening of thiazole-based heterocyclic derivatives as inhibitors of Coronavirus 3CLpro enzymes for the development of COVID-19 therapeutics

Abstract

The enzyme 3-chymotrypsin-like protease (3CLpro) of Coronavirus plays a crucial role in viral replication and is a validated target in the development of new drugs for the treatment of COVID-19. However, till now, most reported 3CLpro inhibitors are raising concerns regarding drug resistance, low efficacy when used as monotherapy. On the other hand, the thiazole scaffold is a privileged structure with potential biological activities. With the aim of finding compounds that can inhibit new 3CLpro enzymatic activity, we applied molecular docking simulations to investigate the interactions between 40 thiazole-based derivatives, including small molecules and Food and Drug Administration (FDA) - approved drugs, with the 3CLpro enzymes of SARS-CoV, MERS-CoV, and particularly SARS-CoV-2. The simulation results revealed that 8 potential compounds are capable of binding directly to the catalytic site of 3CLpro, including edoxaban, ixabepilone, dabrafenib, and ceftaroline fosamil, which exhibited binding affinities to SARSCoV-2 3CLpro of -8.6, -8.7, -8.8, and -8.9 kcal/mol, respectively. This study presents a reliable in silico screening model for the identification of novel 3CLpro inhibitors bearing thiazole scaffolds, contributing to the development of potential antiviral drugs against SARS-CoV-2.