Cheminformatics bioprospection of selected medicinal plants metabolites against trypsin cleaved VP4 (spike protein) of rotavirus A

Abstract

Rotaviruses have continued to be the primary cause of acute dehydrating diarrhoea in children under five years of age despite the global introduction of four World Health Organization (WHO) prequalified oral vaccines in over 106 countries. Currently, no medication is approved by the Food and Drug Administration (FDA) specifically for treating rotavirus A-induced diarrhoea. Consequently, it is important to focus on developing prophylactic and curative therapeutics to combat rotaviral infections. For the first time, this study computationally screened and identified metabolites from Spondias mombin, Macaranga barteri and Dicerocaryum eriocarpum as potential novel inhibitors with broad-spectrum activity against VP5* and VP8* (spike protein) of rotavirus A (RVA). The initial top 20 metabolites identified through molecular docking were further filtered using drug-likeness and pharmacokinetics parameters. The molecular properties of the resulting top-ranked compounds were predicted by conducting density functional theory (DFT) calculations, while molecular dynamics (MD) simulation revealed their thermodynamic compatibility with a significant affinity towards VP8* than VP5*. Except for ellagic acid (−11.78 kcal/mol), the lead compounds had higher binding free energy than the reference standard (VP5* (−11.81 kcal/mol), VP8* (−14.12 kcal/mol)) with 2SG (−20.98 kcal/mol) and apigenin-4'-glucoside (−23.56 kcal/mol) having the highest affinity towards VP5* and VP8*, respectively. Of all the top-ranked compounds, better broad-spectrum affinities for both VP5* and VP8* than tizoxanide were observed in 2SG (VP5* (−20.98 kcal/mol), VP8* (−20.13 kcal/mol)) and sericetin (VP5* (−20.46 kcal/mol), VP8* (−18.31 kcal/mol)). While the identified leads could be regarded as potential modulators of the investigated therapeutic targets for effective management of rotaviral infection, additional in vitro and in vivo evaluation is strongly recommended, and efforts are on-going in this regard. Communicated by Ramaswamy H. Sarma