ABSTRACT
The main-protease (Mpro) catalyzes a crucial step for the SARS-CoV-2 life cycle. The recent SARS-CoV-2 presents the main protease (MCoV2pro) with 12 mutations compared to SARS-CoV (MCoV1pro). 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 MCoV2pro, as well as its implications for ligand accessibility and optimized drug screening. We find a significantly higher accessibility to open binding conformers in the MCoV2pro monomer compared to MCoV1pro. A higher hydration propensity for the MCoV2pro S2 loop with the A46S substitution seems to exercise a key role. Quantum calculations suggest that the wider conformations for MCoV2pro 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 MCoV2pro 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.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/metabolism , Catalytic Domain , Ligands , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Cysteine Endopeptidases/chemistryABSTRACT
The COVID-19 caused by the SARS-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. At present, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 (papain-like, PLpro domain), Nsp5 (Mpro, 3CLpro), Nsp12 (RdRp), Nsp15 (NendoU), N protein, and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations to identify possible new treatments of SARS-CoV-2 infections. The DockThor-VS is freely available at www.dockthor.lncc.br .
