Molecular modelling identification of phytocompounds from selected African botanicals as promising therapeutics against druggable human host cell targets of SARS-CoV-2

Abstract

The coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is highly pathogenic and transmissible. It is mediated by the binding of viral spike proteins to human cells via entry and replication processes involving human angiotensin converting enzyme-2 (hACE2), transmembrane serine protease (TMPRSS2) and cathepsin L (Cath L). The identification of novel therapeutics that can modulate viral entry or replication has been of research interest and would be germane in managing COVID-19 subjects. This study investigated the structure-activity relationship inhibitory potential of 99 phytocompounds from selected African botanicals with proven therapeutic benefits against respiratory diseases focusing on SARS-CoV-2's human cell proteins (hACE2, TMPRSS2, and Cathepsin L) as druggable targets using computational methods. Evaluation of the binding energies of the phytocompounds showed that two compounds, Abrusoside A (-63.393 kcal/mol) and Kaempferol-3-O-rutinoside (-58.939 kcal/mol) had stronger affinity for the exopeptidase site of hACE2 compared to the reference drug, MLN-4760 (-54.545 kcal/mol). The study further revealed that Verbascoside (-63.338 kcal/mol), Abrectorin (-37.880 kcal/mol), and Friedelin (-36.989 kcal/mol) are potential inhibitors of TMPRSS2 compared to Nafamostat (-36.186 kcal/mol), while Hemiphloin (-41.425 kcal/mol), Quercetin-3-O-rutinoside (-37.257 kcal/mol), and Myricetin-3-O-galactoside (-36.342 kcal/mol) are potential inhibitors of Cathepsin L relative to Bafilomycin A1 (-38.180 kcal/mol). The structural analysis suggests that these compounds do not compromise the structural integrity of the proteins, but rather stabilized and interacted well with the active site amino acid residues critical to inhibition of the respective proteins. Overall, the findings from this study are suggestive of the structural mechanism of inhibitory action of the identified leads against the proteins critical for SARS-CoV-2 to enter the human host cell. While the study has lent credence to the significant role the compounds could play in developing potent SARS-CoV-2 candidate drugs against COVID-19, further structural refinement, and modifications of the compounds for subsequent in vitro as well as preclinical and clinical evaluations are underway.

Keywords: COVID-19; Host cell targets; Molecular dynamics simulation; Phytocompounds; SARS-CoV-2.