Discovery of Fungal Metabolites Bergenin, Quercitrin and Dihydroartemisinin as Potential Inhibitors Against Main Protease of SARS-CoV-2

Abstract

Emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has given rise to COVID-19 pandemic, that is wreaking havoc worldwide. Therefore, there is an urgent need to find out novel drugs to combat SARS-CoV-2 infection. In this backdrop, the present study was aimed to assess potent bioactive compounds from different fungi as potential inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) using an <i>in-silico</i> analysis. Nearly 118 bioactive compounds were extracted from <i>Dictyophora indusiata</i>, <i>Geassstrum triplex</i> and <i>Cyathus stercoreus </i>and identified using HR LC/MS analysis. Of which, only bergenin (<i>D. indusiata</i>), quercitrin (<i>G. triplex</i>) and dihydroartemisinin (<i>C. stercoreus</i>) were selected based on their medicinal uses, binding score and active site covered. The 6LU7, a protein crystallographic structure of SARS-CoV-2 M<sup>pro</sup>, was docked with bergenin, quercitrin and dihydroartemisinin using Autodock 4.2 and the binding energies obtained were -7.86, -10.29 and -7.20 kcal/mol, respectively. Bergenin, quercitrin and dihydroartemisinin formed hydrogen bond, electrostatic interactions and hydrophobic interactions with foremost active site amino acids THR190, GLU166, GLN189, GLY143, HIS163, HIS164, CYS145 and PHE140. Present investigation suggests that these three drugs may be used as alternative inhibitors against SARS-CoV-2 M<sup>pro</sup>. However, further research is necessary to assess <i>in vitro</i> potential of these drugs. To the best of our knowledge, present investigation reported these three bioactive compounds of fungal origin for the first time.

Potential SARS-CoV-2 main protease inhibitors

“…8 ) was found to inhibit 11.9% of the SARS-CoV-2 M pro at 50 µM and could be a lead molecule for the development of more potent inhibitors, while taking into account the anti-inflammatory as well as the adverse health risks of this drug.

Figure 8 Molecules most recently reported to demonstrate potential in silico SARS-CoV-2 M pro inhibitory activity 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 .

…”

“…Using molecular docking and MD simulations, Kumar et al [75] reported the compounds withanone and caffeic acid phenethyl ester to be better inhibitors of SARS-CoV-2 than withaferin-A, and they were as equipotent as the covalent protease inhibitor N3. Patel et al [76] showed that fungal metabolites such as bergenin and dihydroartemisinin were slightly better inhibitors than N3 when virtually screened against the SARS-CoV-2 M pro , but not better than the flavonoid glycoside quercitrin. Lyndem et al [77] screened naturally occurring coumarin derivatives and identified corymbocoumarin, methylgalbanate and heraclenol as potential SARS-CoV-2 M pro inhibitors, but they were less potent than control drugs such as lopinavir or ritonavir.…”

Endophytes – untapped resources and pharmacological prospects against coronaviruses

“…44 Fonsecin, a naphthopyrone pigment from Aspergillus fonsecaeus mutant has shown high binding affinity for SARS-COV-2 PLpro by interacting with the Tyr 268 amino acid residue of enzyme cavity based on in silico molecular docking and molecular dynamic studies. 43,45 The genome of Penicillium thymicola contains a polyketide synthase and a nonribosomal peptide synthetase hybrid gene cluster, which upon expression leads to the synthesis of Pyranonigrin A. Pyranonigrin A. is a secondary fungus metabolite with strong inhibitory capability against the SARS-CoV-2 Mpro. 43,46…”

Liquiritin from Glycirrhyza Glabra L (Fabaceae) - A Natural Drug, as a Potent Inhibitor for SARS-CoV-2

“…Furthermore, in adjustment Cox proportional hazard models, patients neither receive combination of drug nor alone one, there were no significant difference in mortality [5]. Nature has always overwhelmed us with many new and unique bioactive compounds which possess potent activity against various disease and infection [6]. Hence, there is prerequisite of scientific community to draw the diverse knowledge of traditional system [7].…”