Effects of theaflavin-gallate in-silico binding with different proteins of SARS-CoV-2 and host inflammation and vasoregulations referring an experimental rat-lung injury

Abstract

Background: SARS-CoV-2 claimed 5,209,104 lives, infected 260,997,910 individuals, globally. Infection is caused due to exposure or susceptibility; deaths occur due to age,comorbidity,higher-viral-load, immuno-suppression, inflammation, and multi-organ failure. Theaflavin-gallate, the major black tea component, showed previous evidence to inhibit HIV-1 Purpose: As theaflavin-gallate prevents experimental rat-lung injury, the study of inhibitory effects of theaflavin-gallate was done, on SARS-CoV-2proteins and various host proteins related to some adverse effects in COVID-19 patients. Study Design: Currently, some prospective phytochemical, black-tea ( Camellia-sinensis ) extract (BTE) was initially tested in vivo in strong oxidant-mutagen arsenic-induced model rat lung injury similar to that of Covid-19 manifestations like severe inflammation, oxidative stress, lung tissue degenerations, and apoptotic death. In silico , extensive bioinformatics and molecular docking experiments were performed on all catechin or theaflavin derivatives of C. sinensis, and finally theaflavin-3’- O -gallate (TFMG) were screened for blocking or inactivation of several proteins of SARS CoV-2 and host adversely-acting proteins or factors. Methods: In vivo experiments in DNA stability (ladder, comet assay), free radicals attack (malondialdehyde; MDA, superoxide dismutase SOD, catalase gel-zymogram assay), extra cellular matrix damage (matrix metalloprotease; MMP2and9 zymogram assay) and inflammation (TNF-α, ELISA). In silico experiments- molecular docking by AutoDock-Patchdock analysis, Surface Topology Calculation by CASTp, Grid-value calculation, and Ramachandran Plot study. Results: The BTE showed strong protection of lung DNA and cell-matrix by decreasing MMPs, TNF-α, and free radicals, the same factors affecting Covid-19 patients. In silico data suggest that TFMG significantly blocked the entry, exit, and amino acids at catalytic active-site of more than thirty proteins including viral (nsp1,nsp2,Mainpro,∼-9.0 kcal/mol) and host inflammatory, oxidants, apoptotic, vaso-destabilizer molecules (FAS, CD40R, BCL2, TLR2, ∼ -10 and ACE1or2 ∼ -9.0 and AT1or2∼ -7.5 kcal/mol and more). When the binding energy of TFMG ranged from -7 to -11.7kcal/mol(average -9.0) the same for hydroxy-Chloroquine ranged (-2.5 to -7 average -4.5) and dexamethasone (-3.0 to -6.0, average -4.0 kcal/mol). Conclusions: TFMG has some novel physicochemical or structural properties like (ACE values of binding to all tested proteins, -300 to -625), (for TFMG H-bond acceptor or donor: 15/10, for TFDG 20/13). Their topological-polar-surface-area (264Ų and 351Ų) and travel depth/height; 17.0/9.6Å and 15.4/11.3Å, respectively) were more potent than other compounds. Concl...

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