Abstract
Bioflavonoids are the largest group of plant-derived polyphenolic compounds with diverse biological potential and have also been proven efficacious in the treatment of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The present investigation validates molecular docking, simulation, and MM-PBSA studies of fifteen bioactive bioflavonoids derived from plants as a plausible potential antiviral in the treatment of COVID-19. Molecular docking studies for 15 flavonoids on the three SARS CoV-2 proteins, non-structural protein-15 Endoribonuclease (NSP15), the receptor-binding domain of spike protein (RBD of S protein), and main protease (Mpro/3CLpro) were performed and selected protein-ligand complexes were subjected to Molecular Dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-PBSA method. All flavonoids were further assessed for their effectiveness as adjuvant therapy by network pharmacology analysis on the target proteins. The network pharmacology analysis suggests the involvement of selected bioflavonoids in the modulation of multiple signaling pathways like p53, FoxO, MAPK, Wnt, Rap1, TNF, adipocytokine, and leukocyte transendothelial migration which plays a significant role in immunomodulation, minimizing the oxidative stress and inflammation. Molecular docking and molecular dynamics simulation studies illustrated the potential of glycyrrhizic acid, amentoflavone, and mulberroside in inhibiting key SARS-CoV-2 proteins and these results could be exploited further in designing future ligands from natural sources.
Highlights
During December 2019, severe acute respiratory syndrome corona virus 2 (SARS-Corona Virus (CoV)-2) emerged as a global pandemic originating from the Wuhan city of China, and still it is a major global threat due to high mortality and morbidity rates
The structural protein protruding on viral surface called spike (S) glycoprotein which exist as a metastable prefusion homotrimeric form enables the entry of 2019-nCoV into the host cells through structural rearrangement
23 residues are missing in the crystal structure in each monomeric chain and these residues were modeled through the Prime module
Summary
During December 2019, severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) emerged as a global pandemic originating from the Wuhan city of China, and still it is a major global threat due to high mortality and morbidity rates. Two-thirds of the genome of all coronoviruses encodes pp1ab, a replicase polyprotein which comprises of two overlapping open reading frames (ORF1a and ORF1b), cleaved into 16 different non-structural proteins (NSPs) by viral proteases [4]. Flavonoids, a group of compounds containing flavan nucleus or a 15-carbon skeleton with two benezene rings linked through pyran ring, are well studied natural compounds comprising more than 6000 structurally well characterized molecules [10] They are reported to possess health benefits in infectious, oncogenic, inflammatory and degenerative diseases [11,12,13,14]. Molecular docking was performed on fifteen potential flavonoids derived from plants against three SARS- CoV-2 proteins namely non-structural protein-15 Endoribonuclease (NSP15), the receptor-binding domain of spike protein (RBD of S protein), and main protease (Mpro, called 3CLpro) as targeted proteins. The top ranking compounds on each protein were subjected to molecular dy namics simulation and Molecular Mechanics Poisson Boltzmann surface area continuum solvation (MM-PBSA) calculations to gain the deeper insights of binding affinity and possible mode of inhibition
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