QSAR Analysis and Molecular Docking Studies of Aryl Sulfonamide Derivatives as Mcl-1 Inhibitors and the Influence of Structure and Chirality on the Inhibitory Activity

IF 1.2 4区医学 Q4 CHEMISTRY, MEDICINAL

Letters in Drug Design & Discovery Pub Date : 2024-02-01 DOI:10.2174/0115701808278918240109053316

Jia Chen, Yang Ma, Jian-Wei Zou, Sheng Hu, Meilan Huang, Guixiang Hu

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Abstract

Background:: Mcl-1 is a kind of antiapoptotic protein and its overexpression is closely related to the occurrence of cancer. Aryl sulfonamide derivatives are expected to become new anticancer agents due to their high inhibitory activity on the Mcl-1 protein. Objective:: The study aimed to establish the QSAR model with good prediction ability and elaborate the influence of structure and chirality on the inhibitory activity. method: Multiple QSAR models were built with different types of descriptors and modeling methods. The molecular docking was performed on compound 45, 25, 26, 24R and 24S. Results:: The comprehensive models including 2D and 3D descriptors demonstrated that nonlinear LSSVM and GP methods gave better results (R2>0.94, RCV2>0.86). The training set had a good predictive power on the test set. The predictive performances of MCCV tests are basically coincident with the results of the single test set. The results of molecular docking showed that the hydrogen bond acceptor at the appropriate position of the substituent on the chiral center can form the hydrogen bond interaction with residue ASN260, which results in the stronger interaction between ligand and protein and higher inhibitory activity. The interaction differences between R and S configuration with Mcl-1 protein are mainly attributed to two residues, HIS224 and ASN260. Two opposite effects lead to the activity of R enantiomer slightly higher than that of S one. The results on chiral compound 24 with ambiguous absolute configuration demonstrated that the steric effect of the substituents on chiral carbon atom is crucial. When there are two substituents with big volume at the same time, high steric effect will prevent the binding of the substituent and the protein, which results in the low inhibitory activity. Conclusion:: The study may provide theoretical guidance on the design and synthesis of novel aryl sulfonamide derivatives with high inhibitory activity

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芳基磺酰胺衍生物作为 Mcl-1 抑制剂的 QSAR 分析和分子对接研究以及结构和手性对抑制活性的影响

背景：Mcl-1 是一种抗凋亡蛋白，其过度表达与癌症的发生密切相关：Mcl-1是一种抗凋亡蛋白，它的过度表达与癌症的发生密切相关。芳基磺酰胺衍生物对 Mcl-1 蛋白具有很高的抑制活性，有望成为新的抗癌药物。研究目的本研究旨在建立具有良好预测能力的 QSAR 模型，并阐述结构和手性对抑制活性的影响：采用不同类型的描述因子和建模方法建立多个 QSAR 模型。对化合物 45、25、26、24R 和 24S 进行了分子对接。结果包括二维和三维描述因子的综合模型表明，非线性 LSSVM 和 GP 方法的结果更好（R2>0.94, RCV2>0.86）。训练集对测试集具有良好的预测能力。MCCV 测试的预测性能与单一测试集的结果基本一致。分子对接结果表明，手性中心取代基适当位置的氢键受体能与残基 ASN260 形成氢键作用，从而使配体与蛋白质之间的相互作用更强，抑制活性更高。R 和 S 构型与 Mcl-1 蛋白的相互作用差异主要归因于 HIS224 和 ASN260 这两个残基。两种相反的作用导致 R 对映体的活性略高于 S 对映体。对绝对构型不明确的手性化合物 24 的研究结果表明，手性碳原子上取代基的立体效应至关重要。当同时存在两个体积较大的取代基时，较高的立体效应会阻碍取代基与蛋白质的结合，从而导致抑制活性较低。结论该研究可为设计和合成具有高抑制活性的新型芳基磺酰胺衍生物提供理论指导

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来源期刊

Letters in Drug Design & Discovery 医学-医药化学

CiteScore

1.80

自引率

10.00%

发文量

245

审稿时长

3 months

期刊介绍： Aims & Scope Letters in Drug Design & Discovery publishes letters, mini-reviews, highlights and guest edited thematic issues in all areas of rational drug design and discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, and structure-activity relationships. The emphasis is on publishing quality papers very rapidly by taking full advantage of latest Internet technology for both submission and review of manuscripts. The online journal is an essential reading to all pharmaceutical scientists involved in research in drug design and discovery.