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3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K.
Bioorg Med Chem. 2006 Apr 15; 14(8):2771-8.BM

Abstract

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.

Authors+Show Affiliations

Pan X
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China.
Tan N
No affiliation info available
Zeng G
No affiliation info available
Han H
No affiliation info available
Huang H
No affiliation info available

MeSH

AldehydesCathepsin KCathepsinsCrystallography, X-RayCysteine Proteinase InhibitorsHumansModels, MolecularQuantitative Structure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16377193

Citation

Pan, Xulin, et al. "3D-QSAR and Docking Studies of Aldehyde Inhibitors of Human Cathepsin K." Bioorganic & Medicinal Chemistry, vol. 14, no. 8, 2006, pp. 2771-8.
Pan X, Tan N, Zeng G, et al. 3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K. Bioorg Med Chem. 2006;14(8):2771-8.
Pan, X., Tan, N., Zeng, G., Han, H., & Huang, H. (2006). 3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K. Bioorganic & Medicinal Chemistry, 14(8), 2771-8.
Pan X, et al. 3D-QSAR and Docking Studies of Aldehyde Inhibitors of Human Cathepsin K. Bioorg Med Chem. 2006 Apr 15;14(8):2771-8. PubMed PMID: 16377193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K. AU - Pan,Xulin, AU - Tan,Ninghua, AU - Zeng,Guangzhi, AU - Han,Hongjin, AU - Huang,Huoqiang, Y1 - 2005/12/27/ PY - 2005/11/02/received PY - 2005/11/24/revised PY - 2005/11/29/accepted PY - 2005/12/27/pubmed PY - 2006/7/13/medline PY - 2005/12/27/entrez SP - 2771 EP - 8 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 14 IS - 8 N2 - 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. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/16377193/3D_QSAR_and_docking_studies_of_aldehyde_inhibitors_of_human_cathepsin_K_ DB - PRIME DP - Unbound Medicine ER -