一种用于设计具有增强细胞毒性特征的克脑文盖尔型吲哚的综合多定量构效关系建模方法。
An Integrated Multi-QSAR Modeling Approach for Designing Knoevenagel- Type Indoles with Enhancing Cytotoxic Profiles.
作者信息
Amin Sk Abdul, Adhikari Nilanjan, Jha Tarun, Gayen Shovanlal
机构信息
Laboratory of Drug Design and Discovery, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar 470003, (MP), India.
Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P.O. Box 17020, Jadavpur University, Kolkata 700032, (WB), India.
出版信息
Curr Comput Aided Drug Des. 2017 Nov 10;13(4):336-345. doi: 10.2174/1573409913666170309150014.
BACKGROUND
Unconventional Knoevenagel-type indoles have been the topic of interest of many synthetic chemists because of its promising efficacy in different diseases including cancer.
OBJECTIVE
To explore the structural requirements of Knoevenagel-type cytotoxic indoles for higher efficacy.
METHODS
Multi-QSAR modeling (MLR, ANN, SVM, Bayesian classification, HQSAR and Topomer CoMFA) was performed on these analogs.
RESULTS
All these modeling techniques were validated individually and interpreted with the experimental SAR observations. Phenyl or p-methoxyphenyl substitution at 2nd position, electron withdrawing groups (such as sulphonyl, cyano etc.) at 3rd position and methoxy substation at 5th position of the indole scaffold may favor cytotoxicity. Eight new indole molecules were predicted from the developed QSAR models.
CONCLUSION
These newly designed compounds may bind to the colchicine binding site of the tubulin protein as suggested by the molecular docking study.
背景
非传统的克诺文纳格尔型吲哚因其在包括癌症在内的不同疾病中显示出有前景的疗效，一直是许多合成化学家感兴趣的主题。
目的
探索克诺文纳格尔型细胞毒性吲哚具有更高疗效的结构要求。
方法
对这些类似物进行了多变量定量构效关系建模（多元线性回归、人工神经网络、支持向量机、贝叶斯分类、全息定量构效关系和拓扑分子场分析）。
结果
所有这些建模技术均单独进行了验证，并结合实验性构效关系观察结果进行了解释。吲哚骨架的第2位苯基或对甲氧基苯基取代、第3位吸电子基团（如磺酰基、氰基等）以及第5位甲氧基取代可能有利于细胞毒性。从所建立的定量构效关系模型中预测了8种新的吲哚分子。
结论
分子对接研究表明，这些新设计的化合物可能与微管蛋白的秋水仙碱结合位点结合。
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