Department of Mathematics and Statistics, Swami Vivekanand Subharti University, Meerut, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, India.
J Biomol Struct Dyn. 2023 Jul;41(10):4650-4666. doi: 10.1080/07391102.2022.2071340. Epub 2022 May 5.
The recent pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) is a viral respiratory disease that has been spread all over the globe. Therefore, it is an urgent requirement to identify and develop drugs for this contagious infection. The papain-like protease (PLpro) of SARS-CoV-2 performs critical functions in virus replication and immune evasion, making it an enticing therapeutic target. SARS-CoV-2 and SARS-CoV PLpro proteases have significant similarities, and an inhibitor discovered for SARS-CoV PLpro is an exciting first step toward therapeutic development. Here, a set of antiviral molecules were screened at the catalytic and S-binding allosteric sites of papain-like protease (PLpro). Molecular docking results suggested that five molecules (44560613, 136277567, S5652, SC75741, and S3833) had good binding affinities at both sites of PLpro. Molecular dynamics analysis like root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and hydrogen bond results showed that identified molecules with PLpro tend to form stable PLpro-inhibitor(s) complexes. Molecular Mechanics/Position-Boltzmann Surface Area (MMPBSA) analysis confirmed that antiviral molecules bound PLpro complex had lower energy (-184.72 ± 7.81 to -215.67 ± 6.73 kJ/mol) complexes. Noticeably, computational approaches revealed promising antivirals candidates for PLpro, which may be further tested by biochemical and cell-based assays to assess their potential for SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
新型严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染（COVID-19）是一种病毒呼吸道疾病，已在全球范围内传播。因此，迫切需要针对这种传染性感染识别和开发药物。SARS-CoV-2 的木瓜样蛋白酶（PLpro）在病毒复制和免疫逃逸中发挥着关键作用，使其成为一个诱人的治疗靶点。SARS-CoV-2 和 SARS-CoV PLpro 蛋白酶具有显著的相似性，针对 SARS-CoV PLpro 的抑制剂是治疗开发的一个令人兴奋的第一步。在这里，一组抗病毒分子在木瓜样蛋白酶（PLpro）的催化和 S 结合变构位点进行了筛选。分子对接结果表明，有五个分子（44560613、136277567、S5652、SC75741 和 S3833）在 PLpro 的两个位点均具有良好的结合亲和力。分子动力学分析（如均方根偏差（RMSD）、均方根波动（RMSF）、回转半径（Rg）、溶剂可及表面积（SASA）和氢键结果）表明，与 PLpro 结合的鉴定分子倾向于形成稳定的 PLpro-抑制剂复合物。分子力学/泊松-玻尔兹曼表面面积（MMPBSA）分析证实，抗病毒分子结合 PLpro 复合物的能量更低（-184.72 ± 7.81 至-215.67 ± 6.73 kJ/mol）。值得注意的是，计算方法揭示了针对 PLpro 的有前途的抗病毒候选药物，这些药物可能通过生化和基于细胞的测定进一步进行测试，以评估它们对 SARS-CoV-2 的潜在用途。由 Ramaswamy H. Sarma 传达。
