In silico approach for uncovering inhibitors of SARS-CoV-2 by targeting TMPRSS2 via molecular networking-based strategies

Abstract

Understanding the pathogenesis of COVID-19 is vital for developing more effective therapeutic strategies. Among the key proteases involved in the disease progression are Transmembrane Serine Protease 2 (TMPRSS2) and Disintegrin and Metalloproteinase 17 (ADAM17), which play critical roles in viral entry and infection. TMPRSS2 facilitates the priming of the SARS-CoV-2 spike (S) protein, making it a promising target for therapeutic intervention. Alpha-1-antitrypsin (A1AT), a natural tissue protector with antiviral and anti-inflammatory properties, inhibits TMPRSS2, further underscoring its importance as a drug target. Given the urgency of addressing the COVID-19 pandemic, repurposing existing FDA-approved drugs offers a faster and more practical approach than developing new drugs from scratch. This study utilized molecular networking strategies via Cytoscape version 3.9.1 to screen FDA-approved drugs for potential interactions with TMPRSS2. A pharmacophore model was subsequently generated, followed by virtual screening and docking studies. From the molecular networking analysis, 22 compounds were selected based on their binding interactions with TMPRSS2. These compounds were evaluated using pharmacophore modeling and virtual screening, with further selection based on Lipinski's rule of five and low RMSD values (below 0.07 Å). Docking studies identified six top-performing molecules from the ZINC database, with ZINC00896543 and ZINC05316843 exhibiting the highest binding affinities (-22.0254 and -21.676 kcal/mol, respectively), surpassing the co-crystal ligand (-12.8236 kcal/mol). The findings highlight the potential of these repurposed compounds for integrated COVID-19 management. Further pharmacokinetic, pharmacodynamic, preclinical, and clinical studies are warranted to validate these candidates and pave the way for designing new agents with minimal side effects and enhanced efficacy.