2020/02/23 by Marina Macchiagodena, Macchiagodena, Marina, Marco Pagliai +3 · 1 citation
Biochemistry, Genetics and Molecular Biology · Chemistry · Computer Science · #Biomolecules (q-bio.BM) #Computational Drug Discovery Methods #FOS: Biological sciences #Protein Structure and Dynamics #Synthesis and biological activity
paper · pdf · doi:10.48550/arxiv.2002.09937
openalex publication_date 2020/02/23 · openalex created_date 2020/03/06 · openalex updated_date 2026/07/28
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.