Exploring Natural Compounds and Synthetic Derivatives As Potential Inhibitors of SARS-CoV-2 PLpro: a Computational Approach with Enzyme Inhibition and Cytotoxicity Assessment

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 (IC value: 1.76 ± 0.17 µM), followed by C2 (IC value; 2.50 ± 0.12 µM) and C1 (IC 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.