Design of new dipeptide inhibitors against SARS-CoV 3CLpro: 3D-QSAR, molecular docking, MD simulation, ADMET studies and retrosynthesis strategy

Abstract

The 3CL protease plays a crucial role in the life cycle of SARS-CoV. This protease is considered an important antiviral target. In the present work, the 3D-QSAR study was performed on a set composed of twenty-six dipeptide SARS-CoV 3CLpro inhibitors in order to propose the new potent anti-SARS agents with a high predicted activity value. The model of CoMSIA/SH is the optimal, with good statistical results presenting a high value of the cross-validation coefficient Q2 = 0.796 and a good value of the determination coefficient R2 = 0.887, the external validation of this model is justified by the high value of the prediction coefficient R2pred = 0.884 and the validation of Globraikh, Roy and Tropsha criteria. The exploitation of the different results provided key information about the structures favored to improve the inhibitory activity against 3CLpro, and has enabled us to propose seven new potent inhibitors with significant predictive activity values, notably compound M-1 with pKipred=7.080. Then, a molecular docking study was performed to determine the binding energy and to identify the key interactions between the receptor (PDB ID: 1WOF) and the ligands. All the newly designed compounds showed low binding energy values as compared to the Remdesivir -8.144 kcal. mol-1 especially for compounds M-5 and M-4 with the binding affinity values -10.022 kcal. mol-1 and -9.727 kcal.mol-1 respectively. In addition, these inhibitors were verified for in silico pharmacokinetic proprieties and toxicity profile using ADMET. Two compounds M-4 and M-5 with potential results in the molecular docking were selected for the molecular dynamic simulation of 100 ns. The MM-GBSA results show that the predicted compound M-5 has the lowest free energy with -38.200 KJ/mol. We exploited the computer-aided synthesis technology using the ASKCOS website to perform a retrosynthetic analysis of compound M-5.