Novel scaffolds identification against Mpro of SARS-CoV-2 using shape based screening and molecular simulation methods

Abstract

BackgroundPfizer in the USA has pioneered an orally active drug called Nirmatrelvir (PF-07321332) targeting the main protease (Mpro) protein of SARS-CoV-2. However, the current scenario demands additional scaffolds with greater potency and binding affinity. MethodsVarious computational techniques were employed to detect the new scaffold in comparison to Mpro. These techniques included shape-based screening, molecular docking, molecular dynamic simulation (MDS), and ADMET studies. The query molecule for the shape-based screening in the ZINC database was PF-07321332. In docking investigations, every screened molecule was assessed for binding mode analysis. The binding strength of the top 10 screened compounds was further examined using the Prime/MMGBSA, Glimpse, and KDeep tools. Only best four of the screened molecules were chosen for stability assessments within Mpro's active site using Gromacs for MDS studies. To validate the Gromacs MDS results, all of these screened molecules were subsequently processed in Desmond software for triplicate MDS investigations (per complex). Significant findingsThrough analysis involving RMSD, RMSF, H-bonding, and the radius of gyration, it was observed that during both MDS studies, the molecules ZINC000073548482, ZINC000036121206, and ZINC000064468475 displayed minimal fluctuations while exhibiting higher binding free energy against Mpro. This suggests that these molecules showcased exceptional stability within Mpro's active site throughout both MDS processes when compared to the reference (6W63). Consequently, these chemically varied screened molecules (ZINC000073548482, ZINC000036121206, and ZINC000064468475) could potentially serve as novel, diverse shape similar scaffolds against Mpro, previously unreported against SARS-CoV-2. However, these claims require experimental validation. The multiple screening methods with both MDS tools found valuable to find the novel scaffolds against Mpro. These scaffolds hold promise for furthering the development of innovative and refined therapeutics targeting Mpro in SARS-CoV-2.