Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India.
Department of Chemistry, Indian Institute of Technology, Delhi, New Delhi, India.
Sci Rep. 2021 Jun 3;11(1):11723. doi: 10.1038/s41598-021-91196-1.
Chronic hepatitis B virus (HBV) infection is a global problem. The loss of hepatitis B surface antigen (HBsAg) in serum is a therapeutic end point. Prolonged therapy with nucleoside/nucleotide analogues targeting the HBV-polymerase may lead to resistance and rarely results in the loss of HBsAg. Therefore, inhibitors targeting HBsAg may have potential therapeutic applications. Here, we used computational virtual screening, docking, and molecular dynamics simulations to identify potential small molecule inhibitors against HBsAg. After screening a million molecules from ZINC database, we identified small molecules with potential anti-HBV activity. Subsequently, cytotoxicity profiles and anti-HBV activities of these small molecules were tested using a widely used cell culture model for HBV. We identified a small molecule (ZINC20451377) which binds to HBsAg with high affinity, with a KD of 65.3 nM, as determined by Surface Plasmon Resonance spectroscopy. Notably, the small molecule inhibited HBsAg production and hepatitis B virion secretion (10 μM) at low micromolar concentrations and was also efficacious against a HBV quadruple mutant (CYEI mutant) resistant to tenofovir. We conclude that this small molecule exhibits strong anti-HBV properties and merits further testing.
慢性乙型肝炎病毒 (HBV) 感染是一个全球性问题。血清乙型肝炎表面抗原 (HBsAg) 的丢失是一种治疗终点。针对 HBV 聚合酶的核苷 (酸) 类似物的长期治疗可能会导致耐药性，很少会导致 HBsAg 的丢失。因此，针对 HBsAg 的抑制剂可能具有潜在的治疗应用。在这里，我们使用计算虚拟筛选、对接和分子动力学模拟来鉴定针对 HBsAg 的潜在小分子抑制剂。在从 ZINC 数据库筛选出一百万个分子后，我们鉴定出了具有潜在抗 HBV 活性的小分子。随后，使用广泛用于 HBV 的细胞培养模型测试了这些小分子的细胞毒性谱和抗 HBV 活性。我们鉴定出一种与 HBsAg 具有高亲和力的小分子 (ZINC20451377)，其 KD 为 65.3 nM，通过表面等离子体共振光谱法测定。值得注意的是，该小分子在低微摩尔浓度下抑制 HBsAg 的产生和乙型肝炎病毒粒子的分泌（10 μM），并且对四种突变体（CYEI 突变体）的乙型肝炎病毒也有效，该突变体对替诺福韦耐药。我们得出结论，这种小分子表现出很强的抗 HBV 特性，值得进一步测试。
