3D-QSAR Studies on C24-Monoalkylated Vitamin D3 26,23-Lactones and their C2α-Modified Derivatives with Inhibitory Activity to Vitamin D Receptor
✍ Scribed by Jinhu Wang; Ke Tang; Qianqian Hou; Xueli Cheng; Lihua Dong; Yongjun Liu; Chengbu Liu
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 2010
- Tongue
- English
- Weight
- 633 KB
- Volume
- 29
- Category
- Article
- ISSN
- 1868-1743
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✦ Synopsis
Abstract
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.