2,4,6-三甲氧基查尔酮衍生物:通过QSAR、分子对接、ADMET预测和计算模拟重新设计作为抗癌剂的新型化学实体的综合研究。

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trupti S Chitre, Aayush M Mandot, Ramali D Bhagwat, Nikhil D Londhe, Atharva R Suryawanshi, Purvaj V Hirode, Aniket L Bhatambrekar, Somdutta Y Choudhari
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引用次数: 0

摘要

QSAR 是一种在药物设计中优化先导化合物的高效而成功的方法,本研究采用 QSAR 对已报道的一系列源自 2,4,6- 三甲氧基查尔酮衍生物的化合物进行了研究。在 QSARINS 模型开发软件的帮助下,研究人员考察了这些化合物抑制 CDK1 的能力。生成的 QSAR 模型揭示了三个重要的描述因子,这些描述因子具有很强的相关性和令人印象深刻的统计值:交叉验证留一相关系数 (Q2LOO) = 0.6663,决定系数 (R2) = 0.7863,外部验证系数 (R2ext) = 0.7854,交叉验证留空相关系数 (Q2LMO) = 0.6256,交叉验证一致相关系数 (CCCcv) = 0.8150,CCCtr = 0.8804,CCCext = 0.8750。根据主要的结构发现以及从描述符 ETA_dPsi_A、WTPT-5 和 GATS7s 中获得的启示,设计出了新的先导分子。然后,利用本研究开发的三描述符模型对所设计的分子的 CDK1 抑制活性进行了评估。为了评估它们的药物可能性,使用 Schrodinger's 软件进行了体内 ADMET 预测。为确定设计化合物与目标蛋白质的相互作用,进行了分子对接。分子动力学模拟的结果证实了所设计的化合物具有出色的结合袋分子稳定性和抗癌效果。这项工作的结果指出了有效抑制蛋白质所必需的重要特性和关键相互作用,为进一步开发新型抗癌剂提出了候选先导化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
2,4,6-Trimethoxy chalcone derivatives: an integrated study for redesigning novel chemical entities as anticancer agents through QSAR, molecular docking, ADMET prediction, and computational simulation.

QSAR, an efficient and successful approach for optimizing lead compounds in drug design, was employed to study a reported series of compounds derived from 2,4,6-trimethoxy chalcone derivatives. The ability of these compounds to inhibit CDK1 was examined, with the help of QSARINS software for model development. The generated QSAR model revealed three significant descriptors, exhibiting strong correlations with impressive statistical values: cross-validation leave-one-out correlation coefficient (Q2LOO) = 0.6663, coefficient of determination (R2) = 0.7863, external validation coefficient (R2ext) = 0.7854, cross-validation leave-many-out correlation coefficient (Q2LMO) = 0.6256, Concordance Correlation Coefficient for cross-validation (CCCcv) = 0.8150, CCCtr = 0.8804, and CCCext = 0.8750. From the key structural findings and the insights gained from the descriptors, ETA_dPsi_A, WTPT-5, and GATS7s, new lead molecules were designed. The designed molecules were then evaluated for their CDK1 inhibitory activity using the three-descriptor model developed in this study. To evaluate their drug likeliness, in-silico ADMET predictions were made using Schrodinger's Software. Molecular docking was carried out to determine the interactions of designed compounds with the target protein. The designed compounds having excellent binding pocket molecular stability and anticancer effectiveness was substantiated by the findings of the molecular dynamics simulation. The results of this work point out important properties and crucial interactions necessary for efficient protein inhibition, suggesting lead candidates for further development as novel anticancer agents.

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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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