Shortlisting Phytochemicals Exhibiting Inhibitory Activity against Major Proteins of SARS-CoV-2 through Virtual Screening

Abstract

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) declared as a pandemic by WHO that has affected more than 40 lakh peoples and caused death of more than 2 lakh individuals across the globe. Limited availability of genomic information of SARS-CoV-2 and non-availability of vaccines and effective drugs are major problems responsible for the ineffective control and management of this pandemic. Several attempts have been made to explore repurposing existing drugs known for their anti-viral activities, and test the traditional herbal medicines known for their health benefiting and immune boosting activity against SARS-CoV-2.In this study, efforts were made to examine the potential of 721 phytochemicals of 37 plant species in inhibiting major protein targets namely, spike glycoprotein, main protease (MPro), NSP3, NSP9, NSP15, NSP10-NSP16 and RNA dependent RNA polymerase of SARS-CoV-2 through virtual screening approach. Results of our experiments revealed that SARS-CoV-2 MPro shared significant dissimilarities against SARS-CoVMPro and MERS-CoVMPro indicating the need for discovering novel drugs. This study has identified the phytochemical cyanin (Zingiber officinale) exhibiting broad spectrum inhibitory activity against main proteases of all the three Coronaviruses. Amentoflavone, agathisflavone, catechin-7-o-gallate and chlorogeninwere shown to exhibit multi target inhibitory activity. This study has identified Mangifera indica, Anacardium occidentale, Vitex negundo, Solanum nigrum, Pedalium murex, Terminalia chebula, Azadirachta indica, Cissus quadrangularis, Clerodendrum serratum and Ocimum basilicum as potential sources of phytochemicals combating nCOVID-19. More interestingly, this study has generated evidences for the anti-viral properties of the traditional herbal formulation “Kabasura kudineer” recommended by AYUSH, a unit of Government of India. Testing of short listed phytochemicals through clinical trials will help in developing effective formulation for management of this pandemic disease. Genomic analysis of identified herbal plants will help in unravelling molecular complexity of therapeutic and anti-viral properties and will pave way for designing synthetic drugs.

A Deadly Embrace: Hemagglutination Mediated by SARS-CoV-2 Spike Protein at Its 22 N-Glycosylation Sites, Red Blood Cell Surface Sialoglycoproteins, and Antibody

“…Competitive binding to viral spike protein by such SA-rich agents as gangliosides [ 41 ] and fetuin [ 80 ], for example, has been studied. Toward the goal of identifying potential therapeutics for COVID-19, four molecular modeling studies collectively screened over 800 molecules for binding to SARS-CoV-2 viral spike protein [ 193 , 194 , 195 , 196 ]. The strongest or close to strongest binding affinity in each study was obtained for ivermectin (IVM), a macrocyclic lactone with multifaceted antiparasitic and antimicrobial activity, distributed in 3.7 billion doses for human diseases worldwide since 1987 [ 197 , 198 , 199 ].…”

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

“…Further, prolonged durations of exposure to a drug likely would require a fraction of the dosing in short term cell model exposure. Further, multiple co-existing or alternate mechanisms of action likely explain the clinical effects observed, such as the competitive binding of ivermectin with the host receptor-binding region of SARS-CoV-2 spike protein, as proposed in six molecular modeling studies (Dayer, 2020;Hussien and Abdelaziz, 2020;Lehrer and Rheinstein, 2020;Maurya, 2020;Nallusamy et al, 2020;Suravajhala et al, 2020). In four of the studies, ivermectin was identified as having the highest or among the highest of binding affinities to spike protein S1 binding domains of SARS-CoV-2 among hundreds of molecules collectively examined, with ivermectin not being the particular focus of study in four of these studies (Scheim, 2020).…”

New bis hydrazone: Synthesis, X-ray crystal structure, DFT computations, conformational study and in silico study of the inhibition activity of SARS-CoV-2

“…When we look at Table 7 which contains the values of binding energy of our molecule and other published inhibitors such as: HDZPA [57] , M1BZP [58] , Hydroxychloroquine [59] and moroxydine [4] with the same receptors. We find that these results give a clear view that 3-Cl BHB has the lowest values of the bending energy compared to the rest of the drugs, which confirms that our ligand have the stronger binding affinity towards M pro and RdRp of SARS-CoV-2.…”