3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K
Pan, XL; Tan, NH; Zeng, GZ; Han, HJ; Huang, HQ
2006-04-15
发表期刊BIOORGANIC & MEDICINAL CHEMISTRY
ISSN0968-0896
卷号14期号:8页码:2771-2778
摘要In order to better understand the structural and chemical features of human cathepsin K (CatK), which is an important cysteine protease in the pathogenesis of osteoporosis, the 3D-QSAR (CoMFA) studies were conducted on recently explored aldehyde compounds with known CatK inhibitory activities. The genetic algorithm of GOLD2.2 has been employed to position 59 aldehyde compounds into the active sites of CatK to determine the probable binding conformation. Good correlations between the predicted binding free energies and the experimental inhibitory activities suggested that the identified binding conformations of these potential inhibitors are reliable. The docking results also provided a reliable conformational alignment scheme for 3D-QSAR model. Based oil the docking conformations, highly predictive comparative molecular field analysis (CoMFA) was performed with q(2) value of 0.723. The predictive ability was validated by some compounds that were not included in the training set. Furthermore, the CoMFA model was mapped back to the binding sites of CatK, to get a better understanding of vital interactions between the aldehyde compounds and the protease. The CoMFA field distributions are in good agreement with the structural characteristics of the binding groove of the CatK, which suggested that the n-Bu in R4 position is the favor group substitute at P1 and moderate groups in R2 group are required oil P2 substitute. In addition, 3D-QSAR results also demonstrated that aldehyde is an important pharmacophore because of electrostatic effect. These results, together with the good correlations between the inhibitory activities and the binding free energies predicted by GOLD2.2, demonstrated the power of combining docking/QSAR approach to explore the probable binding conformations of compounds at the active sites of the protein target, and further provided useful information in understanding the structural and chemical features of CatK in designing and finding new potential inhibitors. (c) 2005 Elsevier Ltd. All rights reserved.
关键词3d-qsar Docking Cathepsin k
收录类别SCI
语种英语
引用统计
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/1813
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources W China, Kunming 650204, Peoples R China
2.Chinese Acad Sci, Grad Sch, Beijing 100039, Peoples R China
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Pan, XL,Tan, NH,Zeng, GZ,et al. 3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2006,14(8):2771-2778.
APA Pan, XL,Tan, NH,Zeng, GZ,Han, HJ,&Huang, HQ.(2006).3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K.BIOORGANIC & MEDICINAL CHEMISTRY,14(8),2771-2778.
MLA Pan, XL,et al."3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K".BIOORGANIC & MEDICINAL CHEMISTRY 14.8(2006):2771-2778.
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