Phytochemicals against SARS-CoV as potential drug leads

Abstract

The newly emerged SARS-CoV-2 strains from the coronavirus (CoV) family is causing one of the most disruptive pandemics of the past century. Developing antiviral drugs is a challenge for the scientific community and pharmaceutical industry. Given the health emergency, repurposing of existing antiviral, antiinflammatory or antimalarial drugs is an attractive option for controlling SARS-CoV-2 with drugs. However, phytochemicals selected based on ethnomedicinal information as well as in vitro antiviral studies could be promising as well. Here, we summarise the phytochemicals with reported anti-CoV activity, and further analyzed them computationally to accelerate validation for drug development against SARS-CoV-2. This systematic review started from the most potent phytocompounds (IC₅₀ in μM) against SARS-CoV, followed by a cluster analysis to locate the most suitable lead(s). The advanced molecular docking used the crystallography structure of SARS-CoV-2-cysteine-like protease (SARS-CoV-2-3CL^pro) as a target. In total, seventy-eight phytochemicals with anti-CoV activity against different strains in cellular assays, were selected for this computational study, and compared with two existing repurposed FDA-approved drugs: lopinavir and ritonavir. This review brings insights in the potential application of phytochemicals and their derivatives, which could guide researchers to develop safe drugs against SARS-CoV-2.

Keywords: Coronavirus; Herbal medicine; MERS; Molecular docking; Natural products; SARS-CoV-2.

Fig. 1

The life cycle of SARS-CoV-2, and probable targets of different antiviral drugs being repurposed or investigated for COVID-19. Abbreviations used: ACE2: angiotensin-converting enzyme 2; HCQ: hydroxychloroquine; TMPRSS2: transmembrane protease serine 2; mRNA: messenger RNA; +ssRNA: positive-strand RNA; pp1ab: polyprotein 1 ab; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment (Adopted from Saha et al. [12]).

Fig. 2

Schematic representation for the localization and function of possible inhibitor classes against 3CL^pro from SARS-CoV-2 (Adopted from Singh et al. [19]).

Fig. 3

Cluster analysis and molecular docking study of phytochemicals with reported anti-CoV activity for potential use against SARS-CoV-2; (1). Cluster analysis of 78 phytochemicals using the ChemMine; tool, (2). Selection of active phytochemicals representing each cluster based on the lowest reported IC₅₀ (μM); (3). Three-dimensional molecular interaction of SARS-CoV-2-3CL^pro (Protein Data Bank ID: 6Y2E) with the most potent phytochemicals from each cluster by BIOVIA-Discovery Studio Visualizer 2.5 software: the AutoDock 4.1 software was used for molecular docking; (4). Two-dimensional interaction visualization by the same BIOVIA-Discovery Studio Visualizer 2.5 software with more clarification on the types of bond formation and interacting amino acids. The light pink dotted line represents the alkyl/pi–alkyl interactions, green the H–bond interaction, light-green for van der Waals and carbon-hydrogen interactions and brick-red color indicates pi-carbon or pi-sulfur, parrot-green shown a pi–loan pair, violet is used for pi-sigma, and dark pink for pi–pi stacked interactions in protein-ligand interaction for each docking complex.

Fig. 4

Molecular docking interaction of 3CL^pro with two repurposed antiviral drugs, lopinavir (A and B) and ritonavir (C and D). Similarly, AutoDock 4.1 and BIOVIA-Discovery Studio Visualizer softwares were used.