Document Detail

3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K.
MedLine Citation:
PMID:  16377193     Owner:  NLM     Status:  MEDLINE    
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 on the docking conformations, highly predictive comparative molecular field analysis (CoMFA) was performed with q2 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 on 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.
Xulin Pan; Ninghua Tan; Guangzhi Zeng; Hongjin Han; Huoqiang Huang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-12-27
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  14     ISSN:  0968-0896     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-03-10     Completed Date:  2006-07-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  2771-8     Citation Subset:  IM    
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China.
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MeSH Terms
Aldehydes / chemistry*,  pharmacology*
Cathepsin K
Cathepsins / antagonists & inhibitors*
Crystallography, X-Ray
Cysteine Proteinase Inhibitors / chemistry*,  pharmacology*
Models, Molecular
Quantitative Structure-Activity Relationship
Reg. No./Substance:
0/Aldehydes; 0/Cysteine Proteinase Inhibitors; EC 3.4.-/Cathepsins; EC protein, human; EC K

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