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3D‐QSAR Studies on C24‐Monoalkylated Vitamin D 3 26,23‐Lactones and their C2 α ‐Modified Derivatives with Inhibitory Activity to Vitamin D Receptor
Author(s) -
Wang Jinhu,
Tang Ke,
Hou Qianqian,
Cheng Xueli,
Dong Lihua,
Liu Yongjun,
Liu Chengbu
Publication year - 2010
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201000071
Subject(s) - quantitative structure–activity relationship , stereochemistry , chemistry , training set , lactone , calcitriol receptor , ligand (biochemistry) , receptor , biochemistry , artificial intelligence , computer science
The ligand‐based three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) for 82 inhibitors of 25‐dehydro‐1 α ‐hydroxyvitamin D 3 ‐26,23‐lactone analogs has been studied by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The established CoMFA model in training set gives a cross‐validated q 2 value of 0.516 and a non‐cross‐validated r ncv 2 value of 0.667, while the CoMSIA model results in q 2 =0.517 and r ncv 2 =0.632. In general, the predictive ability of the CoMFA model is superior to that of the CoMSIA model, with r pred 2 =0.639 for the CoMFA and r pred 2 =0.619 for the CoMSIA model. Based on the CoMFA contour maps, some key structural characters of vitamin D 3 analogs responsible for inhibitory activity are identified, and some new C2 α ‐modified 24‐alkylvitamin D 3 lactone analogs with high predicted p IC 50 values are designed. The ligand functional group mutations by FEP simulation and docking studies reveal the rationality of the molecular design.