Dhanasekaran Sivaraman, Selvadoss Pradeep Pushparaj, Manoharan Solomon Sundar, Jeyabalan Srikanth, Yaraguppi Deepak A, Choudhury Abbas Alam, Rajeswari V Devi, Ramanathan Gnanasambandan, Thamaraikani Tamilanban, Sekar Mahendran, Subramaniyan Vetriselvan, Shing Wong Ling
Department of Biotechnology, School of Energy Technology, Pandit Deendayal Energy University, Knowledge Corridor, Raisan Village, PDPU Road, Gandhinagar, Gujarat, 382426, India.
Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, 600116, India.
Cell Biochem Biophys. 2024 Sep;82(3):2473-2492. doi: 10.1007/s12013-024-01359-w. Epub 2024 Jul 23.
Chronic hepatitis caused by the hepatitis C virus (HCV) is closely linked with the advancement of liver disease. The research hypothesis suggests that the NS5B enzyme (non-structural 5B protein) of HCV plays a pivotal role in facilitating viral replication within host cells. Hence, the objective of the present investigation is to identify the binding interactions between the structurally diverse phytotherapeutics and those of the catalytic residue of the target NS5B polymerase protein. Results of our docking simulations reveal that compounds such as arjunolic acid, sesamin, arjungenin, astragalin, piperic acid, piperidine, piperine, acalyphin, adhatodine, amyrin, anisotine, apigenin, cuminaldehyde, and curcumin exhibit a maximum of three interactions with the catalytic residues (Asp 220, Asp 318, and Asp 319) present on the Hepatitis C virus NS5B polymerase of HCV. Molecular dynamic simulation, particularly focusing on the best binding lead compound, arjunolic acid (-8.78 kcal/mol), was further extensively analyzed using RMSD, RMSF, Rg, and SASA techniques. The results of the MD simulation confirm that the NS5B-arjunolic acid complex becomes increasingly stable from 20 to 100 ns. The orientation of both arjunolic acid and sofosbuvir triphosphate (standard) within the active site was investigated through DCCM, PCA, and FEL analysis, indicating highly stable interactions of the lead arjunolic acid with the catalytic region of the NS5B enzyme. The findings of our current investigation suggest that bioactive therapeutics like arjunolic acid could serve as promising candidates for limiting the NS5B polymerase activity of the hepatitis C virus, offering hope for the future of HCV treatment.
丙型肝炎病毒（HCV）引起的慢性肝炎与肝脏疾病的进展密切相关。研究假设表明，HCV的NS5B酶（非结构5B蛋白）在促进病毒在宿主细胞内复制方面起着关键作用。因此，本研究的目的是确定结构多样的植物疗法与目标NS5B聚合酶蛋白催化残基之间的结合相互作用。我们的对接模拟结果显示，诸如阿朱诺酸、芝麻素、阿朱诺宁、紫云英苷、胡椒酸、哌啶、胡椒碱、刺蒺藜苷、鸭嘴花碱、香树脂醇、山油柑碱、芹菜素、枯茗醛和姜黄素等化合物与HCV丙型肝炎病毒NS5B聚合酶上存在的催化残基（Asp 220、Asp 318和Asp 319）最多表现出三种相互作用。分子动力学模拟，特别是针对最佳结合先导化合物阿朱诺酸（-8.78 kcal/mol），使用RMSD、RMSF、Rg和SASA技术进行了进一步广泛分析。MD模拟结果证实，NS5B-阿朱诺酸复合物从20到100 ns变得越来越稳定。通过DCCM、PCA和FEL分析研究了阿朱诺酸和索磷布韦三磷酸酯（标准品）在活性位点内的取向，表明先导阿朱诺酸与NS5B酶催化区域具有高度稳定的相互作用。我们当前研究的结果表明，像阿朱诺酸这样的生物活性疗法有望成为限制丙型肝炎病毒NS5B聚合酶活性的候选药物，为丙型肝炎治疗的未来带来希望。
