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作为胆固醇酯转移蛋白抑制剂的二苯并二氧杂环庚酮和二苯并二氧杂环己酮衍生物的比较分子力场分析、比较分子相似性指数分析和特征值分析

CoMFA, CoMSIA and eigenvalue analysis on dibenzodioxepinone and dibenzodioxocinone derivatives as cholesteryl ester transfer protein inhibitors.

作者信息

Xiong Xu-qiong, Zhao Dong-mei, Bu Peng-fei, Liu Yang, Ren Jin-hong, Wang Jian, Cheng Mao-sheng

机构信息

Key Lab of New Drugs Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.

出版信息

Molecules. 2008 Aug 22;13(8):1822-39. doi: 10.3390/molecules13081822.

DOI:10.3390/molecules13081822
PMID:18794787
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6245342/
Abstract

CoMFA, CoMSIA and eigenvalue analysis (EVA) were performed to study the structural features of 61 diverse dibenzodioxepinone and dibenzodioxocinone analogues to probe cholesteryl ester transfer protein (CETP) inhibitory activity. Three methods yielded statistically significant models upon assessment of cross-validation, bootstrapping, and progressive scrambling. This was further validated by an external set of 13 derivatives. Our results demonstrate that three models have a good interpolation as well as extrapolation. The hydrophobic features were confirmed to contribute significantly to inhibitor potencies, while a pre-oriented hydrogen bond provided by the hydroxyl group at the 3-position indicated a good correlation with previous SAR, and a hydrogen bond acceptor may play a crucial role in CETP inhibition. These derived models may help us to gain a deeper understanding of the binding interaction of these lactone-based compounds and aid in the design of new potent compounds against CETP.

摘要

进行比较分子场分析（CoMFA）、比较分子相似性指数分析（CoMSIA）和特征值分析（EVA），以研究61种不同的二苯并二氧杂环庚酮和二苯并二氧杂环辛酮类似物的结构特征，从而探究胆固醇酯转移蛋白（CETP）抑制活性。在对交叉验证、自抽样法和逐步扰乱法进行评估时，这三种方法产生了具有统计学意义的模型。这通过一组13种衍生物的外部数据集得到了进一步验证。我们的结果表明，这三个模型具有良好的内插法以及外推法。疏水性特征被证实对抑制剂效力有显著贡献，而3位羟基提供的预定位氢键表明与先前的构效关系有良好的相关性，并且氢键受体可能在CETP抑制中起关键作用。这些推导模型可能有助于我们更深入地理解这些基于内酯的化合物的结合相互作用，并有助于设计针对CETP的新型强效化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/0820bc4462c7/molecules-13-01822-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/56f7eef1c85c/molecules-13-01822-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/5e4a01842ee2/molecules-13-01822-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/42f74425edf7/molecules-13-01822-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/2b09584ebbc3/molecules-13-01822-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/ac765808734e/molecules-13-01822-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/7091cc9fd929/molecules-13-01822-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/d9e2723127fa/molecules-13-01822-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/0820bc4462c7/molecules-13-01822-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/56f7eef1c85c/molecules-13-01822-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/5e4a01842ee2/molecules-13-01822-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/42f74425edf7/molecules-13-01822-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/2b09584ebbc3/molecules-13-01822-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/ac765808734e/molecules-13-01822-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/7091cc9fd929/molecules-13-01822-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/d9e2723127fa/molecules-13-01822-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5dce/6245342/0820bc4462c7/molecules-13-01822-g008.jpg

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