Inhibition of the Main Protease 3CL-pro of the Coronavirus Disease 19 via Structure-Based Ligand Design and Molecular Modeling

TL;DR

This study employs computational methods like virtual screening, docking, and molecular dynamics to identify potential non-covalent inhibitors of the SARS-CoV-2 main protease, revealing promising ligand candidates with stable binding.

Contribution

It introduces a structure-based ligand design approach combined with molecular modeling to discover inhibitors targeting the SARS-CoV-2 main protease.

Findings

Docking shows similar ligand binding in SARS-CoV and SARS-CoV2 proteases.

A chlorophenyl-pyridyl-carboxamide derivative exhibits stable binding in simulations.

Identified ligands share a common aromatic binding pattern.

Abstract

We have applied a computational strategy, based on the synergy of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CL-pro of the SARS-Cov2 Coronavirus. Based on the recently resolved 6LU7 PDB structure, ligands were generated using a multimodal structure-based design and then optimally docked to the 6LU7 monomer. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases, irrespectively of the protonation state of the catalytic CYS-HIS dyad. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement. Molecular dynamics calculations fully confirm the stability in the 3CL-pro binding pocket of the most potent binder identified by docking, namely a chlorophenyl-pyridyl-carboxamide derivative.