Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling

Marina Macchiagodena; Marco Pagliai; Piero Procacci

doi:10.1016/j.cplett.2020.137489

Identification of potential binders of the main protease 3CL^pro of the COVID-19 via structure-based ligand design and molecular modeling

Chem Phys Lett. 2020 Jul:750:137489. doi: 10.1016/j.cplett.2020.137489. Epub 2020 Apr 18.

Authors

Marina Macchiagodena¹, Marco Pagliai¹, Piero Procacci¹

Affiliation

¹ Dipartimento di Chimica "Ugo Schiff", Universitá degli Studi di Firenze, Via della Lastruccia 3, Sesto Fiorentino I-50019 Italy.

Abstract

We have applied a computational strategy, using a combination 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 X-ray structure (PDB code: 6LU7), ligands were generated using a multimodal structure-based design and then docked to the monomer in the active state. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases. 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.

Keywords: 3CL-PRO; 3CL-PRO inhibitor; Binding affinity; COVID-19; Coronavirus; Coronavirus main protease; Molecular docking; Molecular dynamics; SARS-CoV2.