Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Viruses. 2021 Apr 27;13(5):770. doi: 10.3390/v13050770.
Hepatitis B virus (HBV) capsid assembly modulators (CpAMs) have shown promise as potent anti-HBV agents in both preclinical and clinical studies. Herein, we report our efforts in identifying novel CpAM hits via a structure-based virtual screening against a small molecule protein-protein interaction (PPI) library, and pharmacophore-guided compound design and synthesis. Curated compounds were first assessed in a thermal shift assay (TSA), and the TSA hits were further evaluated in an antiviral assay. These efforts led to the discovery of two structurally distinct scaffolds, ZW-1841 and ZW-1847, as novel HBV CpAM hits, both inhibiting HBV in single-digit µM concentrations without cytotoxicity at 100 µM. In ADME assays, both hits displayed extraordinary plasma and microsomal stability. Molecular modeling suggests that these hits bind to the Cp dimer interfaces in a mode well aligned with known CpAMs.
乙型肝炎病毒（HBV）衣壳组装调节剂（CpAMs）在临床前和临床研究中均显示出作为有效抗 HBV 药物的潜力。在此，我们报告了通过针对小分子蛋白质-蛋白质相互作用（PPI）文库进行基于结构的虚拟筛选、药效团引导的化合物设计和合成，来鉴定新型 CpAM 命中物的努力。经过精心筛选的化合物首先在热转移测定（TSA）中进行评估，然后对 TSA 命中物在抗病毒测定中进行进一步评估。这些努力发现了两种结构截然不同的支架，ZW-1841 和 ZW-1847，它们作为新型 HBV CpAM 命中物，均以个位数 µM 的浓度抑制 HBV，而在 100 µM 时无细胞毒性。在 ADME 测定中，两种命中物均表现出非凡的血浆和微粒体稳定性。分子建模表明，这些命中物以与已知 CpAMs 一致的模式结合到 Cp 二聚体界面。
