In silicoapproach identified benzoylguanidines as SARS-CoV-2 main protease (M^pro) potential inhibitors

Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro

“…First, the screening determined if the structures of BZG1-88 could fit into the substrate binding site and interact with the catalytic dyad (His41 and Cys145) 15 . As previously reported, we validated the docking protocol using the redocking method to ensure accuracy 17 .…”

“…The Laarckian Genetic Algorithm (LGA) was used to perform the simulation. We redocked peptide-like inhibitor N3 (6LU7) and alpha-ketoamide inhibitor O6K (6Y2F) to validate our protocol according to parameters previously described by our group 17 .…”

“…Molecular dynamics (MD) simulations were carried out using GROMACS 2018.1 package 21 with CHARMM36 force field 43 from the best pose obtained by molecular docking. In addition, the enzyme topology preparation, calculation, and results analysis were carried out according to our group's description 17 , 44 , 45 . Each enzyme-ligand complex was inserted and centered in a periodic triclinic box (box dimensions: 3.982 × 4.337 × 5.086 nm; box volume: 702.68 nm 3 ), solvated with water TIP3P type and then neutralized with sufficient positive (Na + ) or negative (Cl - ) ions.…”

“…In a previous report, our research group conducted a virtual screening of 313 diverse structures from LMCL. Docking and dynamic molecular simulations performed on the active site of Mpro revealed that the top-ranked compounds were benzoylguanidines (BZG) 17 . Therefore, in the current research, we performed a virtual screening of a specific group of 88 BZG derivatives to explore and understand their potential for inhibiting the active or allosteric sites of Mpro.…”