Department of Chemistry, Faculty of Science Semlalia, Laboratory of Molecular Chemistry, Marrakech, Morocco.
School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, South Africa.
J Biomol Struct Dyn. 2022 Mar;40(5):1915-1929. doi: 10.1080/07391102.2020.1839561. Epub 2020 Oct 29.
The hepatitis C virus is a communicable disease that gradually harms the liver leading to cirrhosis and hepatocellular carcinoma. Important therapeutic interventions have been reached since the discovery of the disease. However, its resurgence urges the need for new approaches against this malady. The NS4B receptor is one of the important proteins for Hepatitis C Virus RNA replication that acts by mediating different viral properties. In this work, we opt to explore the relationships between the molecular structures of biologically tested NS4B inhibitors and their corresponding inhibitory activities to assist the design of novel and potent NS4B inhibitors. For that, a set of 115 indol-2-ylpyridine-3-sulfonamides (IPSA) compounds with inhibitory activity against NS4B is used. A hybrid genetic algorithm combined with multiple linear regressions (GA-MLR) was implemented to construct a predictive model. This model was further used and applied to a set of compounds that were generated based on a pharmacophore modeling study combined with virtual screening to identify structurally similar lead compounds. Multiple filtrations were implemented for selecting potent hits. The selected hits exhibited advantageous molecular features, allowing for favorable inhibitory activity against HCV. The results showed that 7 out of 1285 screened compounds, were selected as potent candidate hits where Zinc14822482 exhibits the best predicted potency and pharmacophore features. The predictive pharmacokinetic analysis further justified the compounds as potential hit molecules, prompting their recommendation for a confirmatory biological evaluation. We believe that our strategy could help in the design and screening of potential inhibitors in drug discovery.Communicated by Ramaswamy H. Sarma.
丙型肝炎病毒是一种传染性疾病，它会逐渐损害肝脏，导致肝硬化和肝细胞癌。自该疾病发现以来，已经取得了重要的治疗干预措施。然而，其再次出现促使人们需要寻找针对这种疾病的新方法。NS4B 受体是丙型肝炎病毒 RNA 复制的重要蛋白之一，通过介导不同的病毒特性发挥作用。在这项工作中，我们选择探索经过生物测试的 NS4B 抑制剂的分子结构与其相应抑制活性之间的关系，以协助设计新型有效的 NS4B 抑制剂。为此，使用了一组具有 NS4B 抑制活性的 115 个吲哚-2-基吡啶-3-磺酰胺（IPSA）化合物。实施了一种混合遗传算法与多元线性回归（GA-MLR）相结合的方法来构建预测模型。该模型进一步用于一组基于药效团建模研究与虚拟筛选相结合生成的化合物，以识别结构相似的先导化合物。进行了多次过滤以选择有效的命中化合物。选择的命中化合物表现出有利的分子特征，有利于对 HCV 的抑制活性。结果表明，从 1285 个筛选的化合物中，选择了 7 个作为潜在的候选有效命中化合物，其中 Zinc14822482 表现出最佳的预测效力和药效团特征。预测的药代动力学分析进一步证明了这些化合物作为潜在的有效命中化合物，促使推荐对其进行确认性的生物学评估。我们相信，我们的策略可以帮助在药物发现中设计和筛选潜在的抑制剂。由 Ramaswamy H. Sarma 传达。
