INTRODUCTION: The bindings of several ribonucleoside triphosphate (NTP) inhibitors to the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are studied herein to identify potential drug-like candidates that can inhibit the replication of the viral genome by RdRp. METHOD: In this study, a guanosine triphosphate (GTP) bound RdRp structure is generated to model the replication initiation state of RdRp. Subsequently, the bindings of 30 NTP inhibitors to the GTP binding site of RdRp are studied in detail by using the molecular docking method. Based on the docking scores, four NTP inhibitors, such as 2'-Cmethyl- adenosine-5′-triphosphate (mATP), 7-deaza-2'-C-methyladenosine-TP (daza-- mATP), 1-N6-Ethenoadenosine-5′-triphosphate (eATP), and Remdesivir-5′-triphosphate (RTP) are shortlisted for further analysis by employing molecular dynamics simulations and binding free-energy methods. RESULTS: These inhibitors are found to bind to RdRp quite strongly, as evident from their relative binding free energies that lie between -31.54±4.54 to -89.46±4.58 kcal/- mol. As the binding of RTP to the GTP site of RdRp generates the most stable complex, which is about 45 kcal/mol more stable than the binding of GTP to RdRp, it is most likely that RTP may inhibit the replication of the Zika viral genome efficiently. CONCLUSION:: However, experimental studies are required to measure the potency of RTP and other drugs before their clinical use.

中文翻译：

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复制起始状态下核苷酸抑制剂与 ZIKA 病毒 NS5 RdRp 的结合

简介：本文研究了几种核糖核苷三磷酸 (NTP) 抑制剂与寨卡病毒 (ZIKV) 的 RNA 依赖性 RNA 聚合酶 (RdRp) 的结合，以确定可以通过 RdRp 抑制病毒基因组复制的潜在药物样候选物。方法：在本研究中，生成了三磷酸鸟苷 (GTP) 结合的 RdRp 结构来模拟 RdRp 的复制起始状态。随后，利用分子对接方法详细研究了30种NTP抑制剂与RdRp GTP结合位点的结合。根据对接分数，四种NTP抑制剂，例如2'-C甲基-腺苷-5'-三磷酸（mATP）、7-脱氮杂-2'-C-甲基腺苷-TP（daza--mATP）、1-N6-乙烯腺苷-5'-三磷酸 (eATP) 和瑞德西韦-5'-三磷酸 (RTP) 入围，通过采用分子动力学模拟和结合自由能方法进行进一步分析。结果：发现这些抑制剂与 RdRp 的结合相当牢固，从它们的相对结合自由能（介于 -31.54±4.54 至 -89.46±4.58 kcal/-mol 之间）可以看出这一点。由于RTP与RdRp的GTP位点结合生成最稳定的复合物，比GTP与RdRp的结合稳定约45 kcal/mol，因此RTP很可能可以有效抑制寨卡病毒基因组的复制。结论：然而，在临床使用之前，需要进行实验研究来测量 RTP 和其他药物的效力。