Yadav R P, Jena N R
Discipline of Natural Sciences, Indian Institute of Information Technology, Design and Manufacturing, Dumna Airport Road, Jabalpur, 482005 India.
In Silico Pharmacol. 2025 Jul 22;13(2):107. doi: 10.1007/s40203-025-00395-5. eCollection 2025.
The NS2B-NS3 protease and the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are interlinked with viral genome replication. Therefore, inhibiting their activities would reduce the viral loads in patients. To identify molecules that can strongly bind to the substrate binding site of the NS2B-NS3 protease of the ZIKV, interactions of several aryl benzoyl hydrazide (ABH) derivatives (10b, 10c, 10g, 11p, and 11q) and some anti-influenza drugs (Zanamivir, Laninamivir, Baloxavir, Oseltamivir, Rimantadine, Peramivir, and Amantadine) with the ZIKV NS2B-NS3 protease are studied herein by using combined density functional theoretic, docking, molecular dynamics (100 ns MD simulations), and free-energy methods. Among these molecules, 11q binds strongly to the ZIKV protease with a ΔG of about - 15.70 ± 2.30 kcal/mol. Its binding to the NS2B-NS3 protease is stronger than the anti-influenza drugs studied herein. Notably, the binding affinity of 11q is found to be approximately 4 kcal/mol more negative than that of SYC-1307, a known allosteric inhibitor of the ZIKV protease. 11q is also found to bind to the NTP and allosteric sites of the ZIKV RdRp. However, the binding of 11q to the NTP site of RdRp is preferred over that of the allosteric site. Interestingly, extending the simulation time to 500 ns did not alter the structure of 11q bound to both ZIKV protease and the NTP site of RdRp. However, 11q showed a higher affinity toward the NS2B-NS3 protease than the NTP site of RdRp. Computed ADMET parameters, Lipinski's rule of five, and binding affinities suggest that 11q would be a better drug candidate against ZIKV infections.
The online version contains supplementary material available at 10.1007/s40203-025-00395-5.
寨卡病毒（ZIKV）的NS2B-NS3蛋白酶和RNA依赖性RNA聚合酶（RdRp）与病毒基因组复制相互关联。因此，抑制它们的活性将降低患者体内的病毒载量。为了鉴定能够与ZIKV的NS2B-NS3蛋白酶的底物结合位点强烈结合的分子，本文采用密度泛函理论、对接、分子动力学（100纳秒分子动力学模拟）和自由能方法研究了几种芳基苯甲酰肼（ABH）衍生物（10b、10c、10g、11p和11q）以及一些抗流感药物（扎那米韦、拉尼米韦、巴洛沙韦、奥司他韦、金刚烷胺、帕拉米韦和金刚乙胺）与ZIKV NS2B-NS3蛋白酶的相互作用。在这些分子中，11q以约-15.70±2.30千卡/摩尔的ΔG与ZIKV蛋白酶强烈结合。它与NS2B-NS3蛋白酶的结合比本文研究的抗流感药物更强。值得注意的是，发现11q的结合亲和力比已知的ZIKV蛋白酶变构抑制剂SYC-1307的结合亲和力约负4千卡/摩尔。还发现11q与ZIKV RdRp的NTP和变构位点结合。然而，11q与RdRp的NTP位点的结合优于变构位点。有趣的是，将模拟时间延长至500纳秒并没有改变11q与ZIKV蛋白酶和RdRp的NTP位点结合的结构。然而，11q对NS2B-NS3蛋白酶的亲和力高于RdRp的NTP位点。计算得到的ADMET参数、Lipinski五规则和结合亲和力表明，11q将是对抗ZIKV感染的更好的药物候选物。
在线版本包含可在10.1007/s40203-025-00395-5获取的补充材料。
