Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulation for the Discovery of Novel SARS-CoV-2 NSP3 Mac1 Domain Inhibitors

被引:3
|
作者
Yazdani, Behnaz [1 ]
Sirous, Hajar [2 ]
Brogi, Simone [2 ,3 ]
Calderone, Vincenzo [3 ]
机构
[1] Univ Cent Catalunya, Univ Vic, Fac Sci & Technol FCT, Biosci Dept, Vic 08500, Spain
[2] Isfahan Univ Med Sci, Bioinformat Res Ctr, Sch Pharm & Pharmaceut Sci, Esfahan 8174673461, Iran
[3] Univ Pisa, Dept Pharm, Via Bonanno 6, I-56126 Pisa, Italy
来源
VIRUSES-BASEL | 2023年 / 15卷 / 12期
关键词
nonstructural proteins; NSP3; macrodomain; Mac1; ADRP; ADP ribose phosphatase; SARS-CoV-2; drug discovery; DRUG DISCOVERY; ADP-RIBOSYLATION; PROTEIN;
D O I
10.3390/v15122291
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 (Delta Gbind) 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.
引用
收藏
页数:21
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