Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulation for the Discovery of Novel SARS-CoV-2 NSP3 Mac1 Domain Inhibitors
Author:
Yazdani Behnaz1ORCID, Sirous Hajar2ORCID, Brogi Simone23ORCID, Calderone Vincenzo3
Affiliation:
1. Bioscience Department, Faculty of Science and Technology (FCT), Universitat de Vic—Universitat Central de Catalunya (Uvic-UCC), 08500 Vic, Spain 2. Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran 3. Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Abstract
Since the emergence of SARS-CoV-2, many genetic variations within its genome have been identified, but only a few mutations have been found in nonstructural proteins (NSPs). Among this class of viral proteins, NSP3 is a multidomain protein with 16 different domains, and its largest domain is known as the macrodomain or Mac1 domain. In this study, we present a virtual screening campaign in which we computationally evaluated the NCI anticancer library against the NSP3 Mac1 domain, using Molegro Virtual Docker. The top hits with the best MolDock and Re-Rank scores were selected. The physicochemical analysis and drug-like potential of the top hits were analyzed using the SwissADME data server. The binding stability and affinity of the top NSC compounds against the NSP3 Mac1 domain were analyzed using molecular dynamics (MD) simulation, using Desmond software, and their interaction energies were analyzed using the MM/GBSA method. In particular, by applying subsequent computational filters, we identified 10 compounds as possible NSP3 Mac1 domain inhibitors. Among them, after the assessment of binding energies (ΔGbind) on the whole MD trajectories, we identified the four most interesting compounds that acted as strong binders of the NSP3 Mac1 domain (NSC-358078, NSC-287067, NSC-123472, and NSC-142843), and, remarkably, it could be further characterized for developing innovative antivirals against SARS-CoV-2.
Funder
Bioinformatics Research Center in Isfahan University of Medical Sciences, Isfahan
Subject
Virology,Infectious Diseases
Reference77 articles.
1. The biological and clinical significance of emerging SARS-CoV-2 variants;Tao;Nat. Rev. Genet.,2021 2. Chemistry and biology of SARS-CoV-2;Gao;Chem,2020 3. Wang, M.-Y., Zhao, R., Gao, L.-J., Gao, X.-F., Wang, D.-P., and Cao, J.-M. (2020). SARS-CoV-2: Structure, biology, and structure-based therapeutics development. Front. Cell. Infect. Microbiol., 10. 4. The evolution and biology of SARS-CoV-2 variants;Telenti;Cold Spring Harb. Perspect. Med.,2022 5. Naqvi, A.A.T., Fatima, K., Mohammad, T., Fatima, U., Singh, I.K., Singh, A., Atif, S.M., Hariprasad, G., Hasan, G.M., and Hassan, M.I. (2020). Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis., 1866.
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