Center for Biomolecular Sciences, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA.
Center for Biomolecular Sciences, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA; Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood Street, IL 60612, USA.
Bioorg Med Chem Lett. 2019 Aug 15;29(16):2349-2353. doi: 10.1016/j.bmcl.2019.06.009. Epub 2019 Jun 8.
Among the many Hepatitis C virus (HCV) genotypes and subtypes, genotypes 1b and 3a are most prevalent in United States and Asia, respectively. A total of 132 commercially available analogs of a previous lead compound were initially investigated against wild-type HCV genotype 1b NS3/4A protease. Ten compounds showed inhibitory activities (IC values) below 10 µM with comparable direct binding affinities (K values) determined by surface plasmon resonance (SPR). To identify pan-genotypic inhibitors, these ten selected compounds were tested against four additional genotypes (1a, 2a, 3a, and 4) and three drug-resistant mutants (A156S, R155K, and V36M). Four new analogs have been identified with better activities against all five tested genotypes than the prior lead compound. Further, the original lead compound did not show activity against genotype 3a NS3/4A, whereas four newly identified compounds exhibited IC values below 33 µM against genotype 3a NS3/4A. Encouragingly, the best new compound F1813-0710 possessed promising activity toward genotype 3a, which is a huge improvement over the previous lead compound that had no effect on genotype 3a. This intriguing observation was further analyzed by molecular docking and molecular dynamics (MD) simulations to understand their different binding interactions, which should benefit future pan-genotypic inhibitor design and drug discovery.
在众多丙型肝炎病毒 (HCV) 基因型和亚型中，基因型 1b 和 3a 分别是美国和亚洲最常见的基因型。最初针对野生型 HCV 基因型 1b NS3/4A 蛋白酶对 132 种市售类似物进行了全面研究。十种化合物显示出抑制活性（IC 值）低于 10 µM，并且通过表面等离子体共振（SPR）确定了可比的直接结合亲和力（K 值）。为了鉴定泛基因型抑制剂，对这十种选定的化合物进行了针对另外四种基因型（1a、2a、3a 和 4）和三种耐药突变体（A156S、R155K 和 V36M）的测试。已经鉴定出四种新的类似物，它们对所有五种测试的基因型的活性均优于先前的先导化合物。此外，原始先导化合物对基因型 3a NS3/4A 没有活性，而四种新鉴定的化合物对基因型 3a NS3/4A 的 IC 值低于 33 µM。令人鼓舞的是，最好的新化合物 F1813-0710 对基因型 3a 表现出有希望的活性，这比先前对基因型 3a 没有影响的先导化合物有了很大的改进。通过分子对接和分子动力学（MD）模拟进一步分析了这一有趣的观察结果，以了解它们不同的结合相互作用，这应该有助于未来的泛基因型抑制剂设计和药物发现。
