  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.
