Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2

Captions: Virtual screening and docking workflow and schematic genomic representation of spike protein. HTVS (High through virtual screening); SP (Standard precision); XP (Extra precision); MDS (Molecular dynamics simulation). S1 (spike protein subunit-1); S2 (spike protein subunit-2); NTD (N terminal domain); RBD (Receptor binding domain); FP (Fusion peptide); HR1 (Heptapeptide repeat sequence 1); HR2 (Heptapeptide repeat sequence 2); TM (Transmembrane domain); CT (Cytoplasm domain). ACE2 (Angiotensin-converting enzyme2); serine protease (TMPRSS2); Bio-0597 and Bio-0357 (Bioactive compounds). [Display omitted] •Host enzyme ACE2 bind with the S1 domain (receptor binding site) of spike protein and TMPRSS2 cleavage the S1/S2 domain.•Protozide and Chrysin having a binding affinity with both the S1 and S2 domains of SARS CoV-2.•Both bioactive compounds can be blocked the interaction of the virus to host enzymes via ACE2 protein and TMPRSS2.•Receptor binding domain-ligand complexes are stable during 50 ns MD simulation. The scientific community is continuously working to discover drug candidates against potential targets of SARS-CoV-2, but effective treatment has not been discovered yet. The virus enters the host cell through molecular interaction with its enzymatic receptors i.e., ACE2 and TMPRSS2, which, if, synergistically blocked can lead to the development of novel drug candidates. In this study, 1503 natural bioactive compounds were screened by HTVS, followed by SP and XP docking using Schrodinger Maestro software. Bio-0357 (protozide) and Bio-597 (chrysin) were selected for dynamics simulation based on synergistic binding affinity on S1 (docking score −9.642 and −8.78 kcal/mol) and S2 domains (-5.83 and −5.3 kcal/mol), and the RMSD, RMSF and Rg analyses showed stable interaction. The DFT analysis showed that the adsorption of protozide/chrysin, the band gap of protozide/chrysin-F/G reduced significantly. From SERS, results, it can be concluded that QDs nanocluster will act as a sensor for the detection of drugs. The docking study showed Bio-0357 and Bio-0597 bind to both S1 and S2 domains through stable molecular interactions, which can lead to the discovery of new drug candidates to prevent the entry of SARS-CoV-2. This in-silico study may be helpful to researchers for further in vitro experimental validation and development of new therapy for COVID-19.