Computational screening of FDA approved drugs of fungal origin that may interfere with SARS-CoV-2 spike protein activation, viral RNA replication, and post-translational modification: a multiple target approach

Abstract

Coronavirus spread is an emergency reported globally, and a specific treatment strategy for this significant health issue is not yet identified. COVID-19 is a highly contagious disease and needs to be controlled promptly as millions of deaths have been reported. Due to the absence of proficient restorative alternatives and preliminary clinical restrictions, FDA-approved medications can be a decent alternative to deal with the coronavirus malady (COVID-19). The present study aims to meet the imperative necessity of effective COVID-19 drug treatment with a computational multi-target drug repurposing approach. This study focused on screening the FDA-approved drugs derived from the fungal source and its derivatives against the SARS-CoV-2 targets. All the selected drugs showed good binding affinity towards these targets, and out of them, bromocriptine was found to be the best candidate after the screening on the COVID-19 targets. Further, bromocriptine is analyzed by molecular simulation and MM-PBSA study. These studies suggested that bromocriptine can be the best candidate for TMPRSS2, Main protease, and RdRp protein.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-021-00089-8.

Keywords: And molecular simulation; COVID-19; Drug repurposing; FDA approved drugs; Molecular docking.

Fig. 1

a Homology model for TMPRSS2, b local quality estimation with a chart for target by SWISS-Modeler, and c predicted sequence alignment of the model target (TMPRSS2) concerning Human Hepsin TMPRSS1

Fig. 2

Docking score of the drugs against the targets

Fig. 3

3D structure interaction of ligand-protein at the left side and 2D interaction of at right side, a 3D structure interaction of Bromocriptine-M^pro protease, b 2D interaction of Bromocriptine-M^pro protease, c 3D structure interaction of N3-M^pro protease, and d 2D interaction of N3-M^pro protease

Fig. 4

3D structure interaction of ligand-protein at the left side and 2D interaction of at right side, a 3D structure interaction of Bromocriptine-RdRp, b 2D interaction of Bromocriptine-RdRp, c 3D structure interaction of Remdesivir-RdRp, and d 2D interaction of Remdesivir-RdRp

Fig. 5

3D structure interaction of ligand-protein at the left side and 2D interaction of at right side, a 3D structure interaction of Bromocriptine-TMPRSS2, b 2D interaction of Bromocriptine-TMPRSS2, c 3D structure interaction of Camostat mesylate-TMPRSS2, and d 2D interaction of Camostat mesylate-TMPRSS2

Fig. 6

Interactive residues of SARS-CoV-2 targets with Bromocriptine and reference compounds

Fig. 7

Target prediction of Bromocriptine

Fig. 8

RMSD plot of bromocriptine with a Main protease (M^pro), b TMPRSS2 and c RdRp

Fig. 9

Interaction analysis of bromocriptine bounds to M^pro binding domain during simulation process. a Binding of bromocriptine with M^pro before molecular simulation study, b Binding of bromocriptine with M^pro with molecular simulation study at 10 ns, c binding of bromocriptine with M^pro with molecular simulation study at 20 ns, d 2D interaction of the bromocriptine with M^pro before molecular simulation study, e 2D interaction of the bromocriptine with M^pro with molecular simulation study at 10 ns, f 2D interaction of the bromocriptine with M^pro with molecular simulation study at 20 ns

Fig. 10

Interaction analysis of bromocriptine bounds to RdRp binding domain during simulation process. a Binding of bromocriptine with RdRp before molecular simulation study, b binding of bromocriptine with RdRp with molecular simulation study at 10 ns, c binding of bromocriptine with RdRp with molecular simulation study at 20 ns, d 2D interaction of the bromocriptine with RdRp before molecular simulation study, e 2D interaction of the bromocriptine with RdRp with molecular simulation study at 10 ns, f 2D interaction of the bromocriptine with RdRp with molecular simulation study at 20 ns

Fig. 11

Interaction analysis of bromocriptine bounds to TMPRSS2 binding domain during simulation process. a Binding of bromocriptine with TMPRSS2 before molecular simulation study, b binding of bromocriptine with TMPRSS2 with molecular simulation study at 10 ns, c binding of bromocriptine with TMPRSS2 with molecular simulation study at 20 ns, d 2D interaction of the bromocriptine with TMPRSS2 before molecular simulation study, e 2D interaction of the bromocriptine with TMPRSS2 with molecular simulation study at 10 ns, f 2D interaction of the bromocriptine with TMPRSS2 with molecular simulation study at 20 ns

Fig. 12

RMSF plot of bromocriptine with a main protease (M^pro), b TMPRSS2 and c RdRp protein

Fig. 13

SASA plot of bromocriptine with a main protease (M^pro), b TMPRSS2 and c RdRp protein

Fig. 14

Rg plot of bromocriptine with a M^pro, b TMPRSS2, c RdRp protein

Fig. 15

MM-PBSA based binding energy calculation