Benzofuran,1,3,4-恶二唑,和1,2,4-三唑是特权杂环部分,其显示针对多种疾病的最有希望和广谱的生物活性。在目前的研究中,苯并呋喃-1,3,4-恶二唑BF1-BF7和苯并呋喃-1,2,4-三唑化合物BF8-BF15通过计算机辅助药物设计(CADD)方法利用基于结构的筛选针对HCVNS5BRNA依赖性RNA聚合酶(RdRp)进行了测试。应用分子对接方法来评估苯并呋喃附加的1,3,4-恶二唑和1,2,4-三唑BF1-BF15分子的结合潜力。苯并呋喃-1,3,4-恶二唑支架BF1-BF7对HCVNS5B酶的结合亲和力(-12.63至-14.04Kcal/mol)比苯并呋喃-1,2,4-三唑支架BF8-BF15(-14.11至-16.09Kcal/mol)低。分子对接研究显示,苯并呋喃-1,2,4-三唑结构基序BF-9(-16.09Kcal/mol)表现出优异的结合亲和力评分,BF-12(-15.75Kcal/mol),和BF-13(-15.82Kcal/mol),分别,与基于苯并呋喃的HCVNS5B抑制剂的标准参考药物奈斯布韦(-15.42Kcal/mol)相比更好。还进行了分子动力学模拟测定,以获得有关酶-化合物相互作用谱和结构稳定性的有价值的见解,这表明,按照MM-PBSA方法,BF-9+NS5B复合物和BF-12+NS5B复合物具有很强的分子间能量,而根据MM-GBSA计算,BF-12+NS5B复合物是最稳定的系统。对所有苯并呋喃-1,2,4-三唑衍生物BF8-BF15的药物相似度和ADMET研究表明,这些化合物具有良好的药物化学特性,与作为药物的所有评估参数一致。分子对接亲和力得分,MM-PBSA/MM-GBSA和MD仿真稳定性分析,药物相似性分析,和ADMET研究评估表明,N-4-氟苯基-S-连接的苯并呋喃-1,2,4-三唑BF-12可能是未来有前途的抗HCVNS5BRdRp抑制剂治疗药物候选药物,与Nesbuvir标准参考药物具有结构一致性。
Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1-BF7 and benzofuran-1,2,4-triazole compounds BF8-BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1-BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1-BF7 showed lesser binding affinities (-12.63 to -14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8-BF15 (-14.11 to -16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (-16.09 Kcal/mol), BF-12 (-15.75 Kcal/mol), and BF-13 (-15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors\' standard reference drug Nesbuvir (-15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme-compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8-BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug.