Unravelling high-affinity binding compounds towards transmembrane protease serine 2 enzyme in treating SARS-CoV-2 infection using molecular modelling and docking studies

Abstract

The coronavirus disease-19 (COVID-19) outbreak that is caused by a highly contagious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a zoonotic pandemic, with approximately 24.5 million positive cases and 8.3 lakhs deaths globally. The lack of effective drugs or vaccine provoked the research for drug candidates that can disrupt the spread and progression of the virus. The identification of drug molecules through experimental studies is time-consuming and expensive, so there is a need for developing alternative strategies like in silico approaches which can yield better outcomes in less time. Herein, we selected transmembrane protease serine 2 (TMPRSS2) enzyme, a potential pharmacological target against SARS-CoV-2, involved in the spread and pathogenesis of the virus. Since 3D structure is not available for this protein, the present study aims at homology modelling and validation of TMPRSS2 using Swiss-model server. Validation of the modelled TMPRSS2 using various online tools confirmed model accuracy, topology and stereochemical plausibility. The catalytic triad consisting of Serine-441, Histidine-296 and Aspartic acid-345 was identified as active binding site of TMPRSS2 using existing ligands. Molecular docking studies of various drugs and phytochemicals against the modelled TMPRSS2 were performed using camostat as a standard drug. The results revealed eight potential drug candidates, namely nafamostat, meloxicam, ganodermanontriol, columbin, myricetin, proanthocyanidin A2, jatrorrhizine and baicalein, which were further studied for ADME/T properties. In conclusion, the study unravelled eight high affinity binding compounds, which may serve as potent antagonists against TMPRSS2 to impact COVID-19 drug therapy.

The inhibitory effects of toothpaste and mouthwash ingredients on the interaction between the SARS-CoV-2 spike protein and ACE2, and the protease activity of TMPRSS2,in vitro

“…For the human TMPRSS2 model, these four ingredients did not clearly bind to the inhibitor-binding site during the docking simulations. However, as the theoretical isoelectric point of TMPRSS2 is 8.58 (M. Pooja et al, 2021), it is presumed that TMPRSS2 is positively charged at the pH of the assay buffer used in this study.…”

“…For the human TMPRSS2 model, these four ingredients did not clearly bind to the inhibitor-binding site during the docking simulations. However, as the theoretical isoelectric point of TMPRSS2 is 8.58 (M. Pooja et al, 2021), it is presumed that TMPRSS2 is positively charged at the pH of the assay buffer used in this study. Therefore, anionic surfactants are more likely to bind to TMPRSS2 than cationic or nonionic surfactants, thereby leading to the induction of protein denaturation and inhibitory effects.…”

Scutellaria barbata D. Don Inhibits the Main Proteases (Mpro and TMPRSS2) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

“…Baicalein, a main ingredient of the TCM herbal formula Shuanghuanglian, has demonstrated anti-viral effects through inhibiting M pro activity [ 61 , 62 ]. Additionally, studies have reported that baicalein significantly affects both ACE2 and TMPRSS2 [ 63 , 64 ]. A notable screening study, suggesting the compound as a candidate for the treatment of SARS-CoV-2, reported that baicalein also binds with the SARS-CoV-2 nonstructural protein 14 (NSP14) [ 65 ].…”

Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer

“…Analysis of the core of the substrate-binding pocket revealed multiple interactions (such as hydrogen bonding with Leu141/Gly143 and Ser144/His163, π–π interactions with Cys145 and His4, and hydrophobic interactions with Met49 and His41), which effectively blocked SARS-CoV-2 replication via noncovalent incorporation [ 68 ]. The relevant studies [ 70 , 71 , 72 ] provided direct data for a better understanding of the molecular mechanisms of Chinese herbal medicine by studying its active ingredients.…”