SARS-CoV-2 entry inhibitors by dual targeting TMPRSS2 and ACE2: An in silico drug repurposing study

Abstract

The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called “entry inhibitors.” For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.

Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization

“…Despite little evidence has been collected about the clinical efficacy of these molecules, researchers largely agree about their limitations due to the rapid viral mutations, underlying resistance. In this context, the development of multitarget inhibitors, able to target different proteins belonging to the viral machinery has been explored as a suitable strategy to overcome viral resistance, improve the overall anti-viral efficacy and largely reduce the multi-drug dose burden [ [47] , [48] , [49] , [50] ]. Moreover, less focus has been given, initially, to other important proteases, such as PL pro , that equally play a pivotal role in the viral replication processes [ 46 , 48 ].…”

Target-Based In Silico Screening for Phytoactive Compounds Targeting SARS-CoV-2

“…On the other hand, in silico screening could provide a cost-effective method to identify bioactive molecules from different compound sources. A combination approach such as targeting multiple pathogenic pathways and viral proteins may represent a better strategy against the current virus outbreaks [ 54 ]. In this study, we performed in silico screening targeting four critical SARS-CoV-2 viral enzymes, NSP3-PLpro, NSP5-Mpro, NSP12-RdRp, and NSP16-2OMT, aiming to provide a pool of natural compounds with potential for attenuation of pathologic virulence of SARS-CoV-2 and prevention of COVID-19 infection.…”

Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations

“…Alongside the development of new, often high-budget drugs, different strategies were applied in parallel with drug repurposing which remains the best approach to rapidly identify antiviral plausible therapeutic agents. Accordingly, computational approaches to identify suitable and adequate therapeutic options in the short-term and loss-cost, to explore possible interactions with viral proteins have been well investigated [ 13 , 14 ]. The molecular docking and dynamic simulation process were largely applied in structure-based drug design owing to their ability to predict, with reliable accuracy which are intended to decipher the mechanism of binding interactions [ 15 , 16 ].…”