Computational insights into a protease inhibitor from Streptomyces globosus VITSMAB-2 molecular docking and dynamics simulations against SARS-CoV-2 main protease

Abstract

Abstract Viral proteases are critical components in the life cycles of many dangerous viruses, playing a direct role in facilitating viral replication. Targeting these enzymes through inhibition offers a promising strategy for advancing antiviral agents. This study explores the potential of pigmented actinomycetes from high-altitude terrestrial environments as sources of antiviral agents against SARS-CoV-2, with a particular focus on identifying protease inhibitors. From this unique ecological niche, Streptomyces globosus VITSMAB2 was isolated and identified as a promising candidate due to its significant protease-inhibiting capabilities. Both qualitative and quantitative assays confirmed its strong inhibitory activity against key proteases, especially cysteine and serine proteases such as papain and trypsin. Protease inhibitory compounds were partially purified using Ultra-Performance Liquid Chromatography (UPLC), and their identities were determined through Gas Chromatography–Mass Spectrometry (GC-MS) analysis. Among the identified compounds, phenyl carbamate was the most prevalent and emerged as the lead molecule as protease inhibitor. Molecular docking studies revealed that phenyl carbamate exhibited strong binding interactions with the main protease (M-pro) of SARS-CoV-2, highlighting its potential as an antiviral agent. Additionally, assessments of the compound’s drug-likeness and ADME/T (absorption, distribution, metabolism, excretion, and toxicity) profiles indicated favorable pharmacokinetic properties, supporting its candidacy for therapeutic development. Molecular dynamics simulations further confirmed the stability of the phenyl carbamate-M-protease complex, reinforcing the compound’s antiviral potential. Therefore, phenyl carbamate shows considerable promise as a lead antiviral compound and merits further validation through extensive in vitro and in vivo experimentation to fully assess its therapeutic efficacy.