MOLECULAR MODELING STUDIES OF BENZIMIDAZOLYL-CHALCONES AS ANTILEISHMANIAL AGENTS USING QSAR, DOCKING, ADME AND MOLECULAR DYNAMICS STUDIES

Deto N'guessan, A. A. Alzain, Eunice Melissa Adouko, Diomandé Sékou, S. Coulibaly, M. Ouattara
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引用次数: 1

Abstract

Introduction: Present leishmaniasis treatment regimen has many limitations including severe adverse effects, toxicity, and Leishmania strains resistance. In the present study, the objective is to perform QSAR, molecular docking and ADME prediction studies on benzimidazolylchalcones in order to select an antileishmanial drug candidate.Materials & methods: QSAR models were performed on 12 benzimidazolylchalcones with antileishmanial activities against promastigote strains of L. donovani. Binding free energy calculations were performed using MM-GBSA to assess the affinity of the ligands for the proteins. In addition, the three most active compounds (4a-c, IC50 <1-μM) were docked with the protein phosphodiesterase B1 (PDB ID: 2JK6).Results and Discussion: The optimum model has squared correlation coefficient (R2) of 0.983, and leave-one-out (LOO) cross-validation coefficient (Q2CV) value of 0.942. The number of descriptors involved in the model is acceptable (R2 - Q2CV = 0.041), which confirms the model’s stability and validates the developed model’s predictive power. Docking studies revealed that the best compound 4c formed hydrogen bond with SER 464, pi-cation contact with LYS 61 and hydrophobic interactions with LEU 62, TYR 64 and LEU72 of the active site of L. donovani phosphodiesterase B1. ADME properties results showed that all three molecules have good pharmacokinetic properties.Conclusion: Finally, molecular dynamics simulation studies at 30 ns revealed stable interactions with the 2JK6 protein. This study validates the choice of the ortho-chlorinated derivative of benzimidazolylchalcones as the lead compound for developing new derivatives with optimized antileishmanial properties.
利用qsar、对接、adme和分子动力学研究苯并咪唑查尔酮抗利什曼病药物的分子模型
目前利什曼病的治疗方案存在严重的不良反应、毒副作用和利什曼原虫耐药等局限性。本研究的目的是对苯并咪唑基查尔酮进行QSAR、分子对接和ADME预测研究,以筛选抗利什曼原虫候选药物。材料与方法:对12种具有抗利什曼原虫活性的苯并咪唑查尔酮进行QSAR模型研究。结合自由能计算采用MM-GBSA评估配体对蛋白质的亲和力。此外,三个活性最高的化合物(4a-c, IC50 <1-μM)与蛋白磷酸二酯酶B1 (PDB ID: 2JK6)对接。结果与讨论:最优模型的平方相关系数(R2)为0.983,留一交叉验证系数(Q2CV)为0.942。模型中涉及的描述符数量是可以接受的(R2 - Q2CV = 0.041),证实了模型的稳定性,验证了所建立模型的预测能力。对接研究发现,最佳化合物4c与SER 464形成氢键,与LYS 61形成阳离子接触,与L. donovani磷酸二酯酶B1活性位点的LEU 62、TYR 64和LEU72形成疏水相互作用。ADME性质结果表明,三种分子均具有良好的药动学性质。结论:最后,30 ns的分子动力学模拟研究显示了与2JK6蛋白的稳定相互作用。本研究验证了选择苯并咪唑基查尔酮的正氯代衍生物作为先导化合物来开发具有优化抗利什曼动物性能的新衍生物的可行性。
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