A higher flexibility at the SARS-CoV-2 main protease active site compared to SARS-CoV and its potentialities for new inhibitor virtual screening targeting multi-conformers

Rocha, Rafael E. O.; Chaves, Elton J. F.; Fischer, Pedro H. C.; Costa, Leon S. C.; Grillo, Igor Barden; da Cruz, Luiz E. G.; Guedes, Fabiana C.; da Silveira, Carlos H.; Scotti, Marcus T.; Camargo, Alex D.; Machado, Karina S.; Werhli, Adriano V.; Ferreira, Rafaela S.; Rocha, Gerd B.; de Lima, Leonardo H. F.

The main-protease (M(pro)) catalyzes a crucial step for the SARS-CoV-2 life cycle. The recent SARS-CoV-2 presents the main protease (M(CoV2)(pro)) with 12 mutations compared to SARS-CoV (M(CoV1)(pro)). Recent studies point out that these subtle differences lead to mobility variances at the active site loops with functional implications. We use metadynamics simulations and a sort of computational analysis to probe the dynamic, pharmacophoric and catalytic environment differences between the monomers of both enzymes. So, we verify how much intrinsic distinctions are preserved in the functional dimer of M(CoV2)(pro), as well as its implications for ligand accessibility and optimized drug screening. We find a significantly higher accessibility to open binding conformers in the M(CoV2)(pro) monomer compared to M(CoV1)(pro). A higher hydration propensity for the M(CoV2)(pro) S2 loop with the A46S substitution seems to exercise a key role. Quantum calculations suggest that the wider conformations for M(CoV2)(pro) are less catalytically active in the monomer. However, the statistics for contacts involving the N-finger suggest higher maintenance of this activity at the dimer. Docking analyses suggest that the ability to vary the active site width can be important to improve the access of the ligand to the active site in different ways. So, we carry out a multiconformational virtual screening with different ligand bases. The results point to the importance of taking into account the protein conformational multiplicity for new promissors anti M(CoV2)(pro) ligands. We hope these results will be useful in prospecting, repurposing and/or designing new anti SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma