Karpiński Tomasz M, Ożarowski Marcin, Silva Pedro J, Stasiewicz Mark, Alam Rahat, Samad Abdus
Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Rokietnicka 10, 60-806 Poznań, Poland.
Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants-National Research Institute, Wojska Polskiego 71b, 60-630 Poznań, Poland.
Pathogens. 2023 Jun 18;12(6):842. doi: 10.3390/pathogens12060842.
Hepatitis C virus (HCV) is a dangerous virus that is responsible for a large number of infections and deaths worldwide. In the treatment of HCV, it is important that the drugs are effective and do not have additional hepatotoxic effects. The aim of this study was to test the in silico activity of 1893 terpenes against the HCV NS5B polymerase (PDB-ID: 3FQK). Two drugs, sofosbuvir and dasabuvir, were used as controls. The GOLD software (CCDC) and InstaDock were used for docking. By using the results obtained from PLP.Fitness (GOLD), pKi, and binding free energy (InstaDock), nine terpenes were finally selected based on their scores. The drug-likeness properties were calculated using Lipinski's rule of five. The ADMET values were studied using SwissADME and pkCSM servers. Ultimately, it was shown that nine terpenes have better docking results than sofosbuvir and dasabuvir. These were gniditrin, mulberrofuran G, cochlearine A, ingenol dibenzoate, mulberrofuran G, isogemichalcone C, pawhuskin B, 3-cinnamyl-4-oxoretinoic acid, DTXSID501019279, and mezerein. Each docked complex was submitted to 150 ns-long molecular dynamics simulations to ascertain the binding stability. The results show that mulberrofuran G, cochlearine A, and both stereoisomers of pawhuskin B form very stable interactions with the active site region where the reaction product should form and are, therefore, good candidates for use as effective competitive inhibitors. The other compounds identified in the docking screen either afford extremely weak (or even hardly any) binding (such as ingenol dibenzoate, gniditrin, and mezerein) or must first undergo preliminary movements in the active site before attaining their stable binding conformations, in a process which may take from 60 to 80 ns (for DTXSID501019279, 3-cinnamyl-4-oxoretinoic acid or isogemichalcone C).
丙型肝炎病毒（HCV）是一种危险的病毒，在全球导致大量感染和死亡。在HCV治疗中，药物有效且无额外肝毒性作用很重要。本研究的目的是测试1893种萜类化合物对HCV NS5B聚合酶（PDB-ID：3FQK）的计算机模拟活性。两种药物，索磷布韦和达沙布韦用作对照。使用GOLD软件（CCDC）和InstaDock进行对接。通过使用从PLP.Fitness（GOLD）、pKi和结合自由能（InstaDock）获得的结果，最终根据得分选择了9种萜类化合物。使用Lipinski的五规则计算类药性质。使用SwissADME和pkCSM服务器研究ADMET值。最终结果表明，9种萜类化合物的对接结果优于索磷布韦和达沙布韦。它们是gniditrin、桑呋喃G、耳草碱A、二苯甲酸千金二萜醇酯、桑呋喃G、异宝石查耳酮C、泡桐素B、3-肉桂基-4-氧代视黄酸、DTXSID501019279和瑞香毒素。每个对接复合物都进行了150纳秒长的分子动力学模拟，以确定结合稳定性。结果表明，桑呋喃G、耳草碱A以及泡桐素B的两种立体异构体与反应产物应形成的活性位点区域形成非常稳定的相互作用，因此，它们是用作有效竞争性抑制剂的良好候选物。对接筛选中鉴定出的其他化合物要么提供极其微弱（甚至几乎没有）的结合（如二苯甲酸千金二萜醇酯、gniditrin和瑞香毒素），要么必须先在活性位点进行初步移动，然后才能达到其稳定的结合构象，这个过程可能需要60到80纳秒（对于DTXSID501019279、3-肉桂基-4-氧代视黄酸或异宝石查耳酮C）。
