Computational screening of potential bromodomain-containing protein 2 inhibitors for blocking SARS-CoV-2 infection through pharmacophore modeling, molecular docking and molecular dynamics simulation

Abstract

Recently, human bromodomain-containing protein 2 (BRD2) has been reported as a potential drug target in host cells to combat SARS-CoV-2 as well as to treat COVID-19. In this study, we aimed to screen potential BRD2 inhibitors as anti- SARS-CoV-2 agents through computational approach. A pharmacophore model was generated with crystal structure of BRD2 in complex with RVX208 using ZINCPharmer server, and 10,842 compounds were screened from ZINC15 database against the pharmacophore model. Next, 102 compounds exhibited more affinity to BRD2 than control compound (RVX208) were screened using molecular docking. The top five hits (ZINC20417563, ZINC12322175, ZINC12391479, ZINC13098192, and ZINC20407881), which showed docking affinity to BRD2 with −10, −9.9, −9.8, −9.7 and −9.7 kcal/mol, respectively, were subjected to 100 ns molecular dynamics simulation to evaluate the stability of docked complexes and their interaction mechanisms. The appropriate stability of these complexes was displayed, and these compounds were found to be closely adhered to the binding site of the BRD2 protein based on the global dynamics analysis with RMSD, RMSF, Rg, SASA, DSSP and H-bond. The essential dynamics analysis with principal component analysis, dynamic cross-correlation matrix, and free energy landscape showed BRD2 binding of the screened compounds remained the stable conformation throughout molecular dynamics simulation. In addition, the pharmacokinetic and ADMET properties of the five compounds showed these compounds could be potential drug candidates. The findings of this study may contribute to further examinational validation and rational design of novel BRD2 inhibitors as anti-SARS-CoV-2 agents.