Exploring natural compounds and synthetic derivatives as potential inhibitors of SARS-CoV-2 PLpro: a computational approach with enzyme inhibition and cytotoxicity assessment
Shahkaar Aziz, Sana Khan, Alaa Karkashan, Noreen Asim, Khulud Bukhari, Rand Mohammad Almousa, Zafar Ali Shah, Khaled S. Allemailem, Wafa Abdullah I. Al‐Megrin · Journal of Biomolecular Structure and Dynamics · 2025
To address coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), there is a pressing need for direct-acting antiviral medications. Papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is central to viral replication and detrimentally affects the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 proteins. Consequently, targeting PLpro with small-molecule therapeutics offers a promising strategy to effectively inhibit the virus and mitigate its impact on the host’s immune system. Employing a multifaceted computational approach, we identified three phytochemicals demonstrating substantial molecular interactions and binding affinity [α-lapachone (C1) −37.82 ± 0.08 kcal/mol, Lapachol (C2) −48.56 ± 0.04 kcal/mol and Peshawarquinone (C3) −46.64 ± 0.03 kcal/mol)] with PLpro. Molecular dynamics simulations indicated that these compounds formed stable complexes with the naphthalene-inhibitor binding site, inducing a closed PLpro conformation and altering its normal function. Besides, they are predicted to possess favorable physicochemical, pharmacokinetics and drug-like properties. Among these compounds, C3 exhibited the most potent inhibitory potential (IC50 value: 1.76 ± 0.17 µM), followed by C2 (IC50 value; 2.50 ± 0.12 µM) and C1 (IC50 value: 3.42 ± 0.17 µM). Furthermore, evaluating the cytotoxicity of C1–C3 on human BJ cells revealed minimal harmful effects at a 50 µM dosage. These findings suggest that evaluated compounds hold therapeutic promise and could become potential drug candidates for treating SARS-CoV-2.