Strong Binding of Leupeptin with TMPRSS2 Protease May Be an Alternative to Camostat and Nafamostat for SARS-CoV-2 Repurposed Drug: Evaluation from Molecular Docking and Molecular Dynamics Simulations

Abstract

The unprecedented coronavirus SARS-CoV-2 outbreak at Wuhan, China, caused acute respiratory infection to humans. There is no precise vaccine/therapeutic agents available to combat the COVID-19 disease. Some repurposed drugs are saving the life of diseased, but the complete cure is relatively less. Several drug targets have been reported to inhibit the SARS-CoV-2 virus infection, in that TMPRSS2 (transmembrane protease serine 2) is one of the potential targets; inhibiting this protease stops the virus entry into the host human cell. Camostat mesylate, nafamostat, and leupeptin are the drugs, in which the first two drugs are being used for COVID-19 and leupeptin also tested. To consider these drugs as the repurposed drug for COVID-19, it is essential to understand their binding affinity and stability with TMPRSS2. In the present study, we performed the molecular docking and molecular dynamics (MD) simulation of these molecules with the TMPRSS2. The docking study reveals that leupeptin molecule strongly binds with TMPRSS2 protein than the other two drug molecules. The RMSD and RMSF values of MD simulation confirm that leupeptin and the amino acids of TMPRSS2 are very stable than the other two molecules. Furthermore, leupeptin forms interactions with the key amino acids of TMPRSS2 and the same have been maintained during the MD simulations. This structural and dynamical information is useful to evaluate these drugs to be used as repurposed drugs, however, the strong binding profile of leupeptin with TMPRSS2, suggests, it may be considered as a repurposed drug for COVID-19 disease after clinical trial.

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“…Some researchers investigated potential damages of inhibition aimed at host receptor proteins. Parts of molecular modeling studies aimed to block host proteins relating to SARS-CoV-2 attachment, such as ACE2, ,,,− TMPRSS2, ,,,− furin, , and glucose regulated protein 78 (GRP78) . However, according to some reports, it is controversial to design SARS-CoV-2 inhibitors targeting host ACE2s or related proteins.…”

Host Cell Proteases Mediating SARS-CoV-2 Entry: An Overview

“…Homology modeling QM/MM-MD Structural analysis of TMPRSS2 bonding with Camostat and its metabolite GBPA [49] Homology modeling QM/MM-MD Structural analysis of TMPRSS2 bonding with Nafamostat +Camostat and its metabolite GBPA [47] Homology modeling + Pharmacophore + Docking + MD Four non-covalent inhibitors (Otamixaban, UK-1, NCGC00386945, and NCGC00487181) against TMPRSS2 are still less effective than camostat and nafamostat [50] Homology Modeling + MD Non-target binding study of nafamostat and camostat [51] MD MD analysis of binding nafamostat, camostat, gabexate, Bromhexine [52] Homology modeling + Virtual screening + Docking 156 small molecules proposed to have an excellent inhibition profile against TMPRSS2 [53] Homology modeling + Docking + MD Allosteric binding site BH [48] Homology modeling + Docking + MD Three phytochemicals (Niazirin, Quercetin, and Moringyne) are better than camostat [54] Homology modeling + Docking + MD Cepharanthine is better than camostat [55] Homology Homology modeling + Docking + MD bisdemethoxycurcumin (BDMC), carvacrol, and thymol have better inhibition than camostat [62] Homology modeling + Docking + MD Robinin, Daidzin, and Hydroxytuberosonehave potential inhibition profile against TMPRSS2 [63] Homology modeling + Docking + MD structural analysis of TMPRSS bonding with camo + nafamostat+ bromhexine [64] Homology moeling + Docking + MD Structural analysis of TMPRSS2 binding with nafa+camostat+gabexate +sivelestat [65] Homology modeling + Docking + MD 5 phytochemicals against TMPRSS2 [66] Homology modeling + Docking + MD Withaferin A + Withanolide D has a dual inhibition profile targeting TMPRSS2 and ACE2 [67] Docking + MD Ibrutinib and zanubrutinib may have multiple inhibition profiles against TMPRSS and viral proteins [68] Homology modeling + Docking + MD Withanone and Withaferin A may have a better inhibition profile than camostat [69] Homology modeling + Docking + MD benzquercin proposed as a robust TMPRSS2 inhibitor [70] Homology modeling + Docking + MD Leupeptin may be a good alternative for camostat [71] H, K, L, O, S, V, W, and X) [84]. Among all cathepsins, an abundance of cathepsin B and L is noticed [85].…”

Mechanistic insights of key host proteins and potential repurposed inhibitors regulating SARS‐CoV‐2 pathway

“… 17 Additionally, pharmacological studies in human cell lines have indicated the drug Silmitasertib (currently in phase 2 trials) to have high inhibitory activity of CK2 kinases, suggesting the role of these kinases in the SARS‐CoV‐2 life cycle. 17 Previous studies 18 , 19 , 20 on SARS‐CoV have shown that drugs Nafamostat 18 , 19 and Camostat 21 are potential candidates to stop viral entry by binding to transmembrane protease serine 2 (TMPRSS2) proteases. 22 , 23 , 24 However, even at higher concentrations, Camostat showed 65% inhibition of protease binding, and 35% virus entry takes place via the endosomal cathepsin pathway.…”