3D QSAR studies on ketoamides of human cathepsin K inhibitors based on two different alignment methods

被引：21

作者：

Pan, Xulin ^{[1
]}

Tan, Ninghua ^{[1
]}

Zeng, Guangzhi ^{[1
]}

Huang, Huoqiang ^{[1
,2
]}

Yan, He ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, State Key Lab Phytochem & Plant Resources W China, Kunming Inst Bot, Kunming 650204, Peoples R China

[2] Chinese Acad Sci, Grad Sch, Beijing 10049, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 45卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Cathepsin K; CoMFA; CoMSIA; Ketoamides; GENETIC ALGORITHM; BONE-RESORPTION; POTENT; SCAFFOLD; DOCKING; DESIGN; P-1';

D O I：

10.1016/j.ejmech.2009.11.010

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 64 ketoamides as human cathepsin K (CatK) inhibitors, using ROCS ligand-based alignment and receptor-based alignment. Results generated from the ligand-based model were found to be superior to those obtained by the receptor-based model. CoMFA and CoMSIA field distributions are in good agreement with the structural characteristics of the binding groove of CatK, suggesting moderate substitutes at the P1, P2, P3 and P1' may favor the inhibitory activity of ketoamides. These results provide useful information in understanding the structural and chemical features of CatK in designing and finding novel potential CatK inhibitors as osteoporosis therapeutic agents. (C) 2009 Elsevier Masson SAS. All rights reserved.

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收藏

页码：667 / 681

页数：15

相关论文

共 27 条

[1] Dipeptide nitrile inhibitors of cathepsin K [J].

Altmann, E ;

Aichholz, R ;

Betschart, C ;

Buhl, T ;

Green, J ;

Lattmann, R ;

Missbach, M .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (09) :2549-2554

[2] Arylaminoethyl amides as inhibitors of the cysteine protease cathepsin K -: Investigating P1′ substituents [J].

Altmann, E ;

Green, J ;

Tintelnot-Blomley, M .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (12) :1997-2001

[3] 2-cyano-pyrimidines: A new chemotype for inhibitors of the cysteine protease cathepsin K [J].

Altmann, Eva ;

Aichholz, Reiner ;

Betschart, Claudia ;

Buhl, Thomas ;

Green, Jonathan ;

Irie, Osamu ;

Teno, Naoki ;

Lattmann, Rene ;

Tintelnot-Blomley, Marina ;

Missbach, Martin .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (04) :591-594

[4] S3 to S3′ subsite specificity of recombinant human cathepsin K and development of selective internally quenched fluorescent substrates [J].

Alves, MFM ;

Puzer, L ;

Cotrin, SS ;

Juliano, MA ;

Juliano, L ;

Brömme, D ;

Carmona, AK .

BIOCHEMICAL JOURNAL, 2003, 373 :981-986

[5] P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K [J].

Barrett, DG ;

Boncek, VM ;

Catalano, JG ;

Deaton, DN ;

Hassell, AM ;

Jurgensen, CH ;

Long, ST ;

McFadyen, RB ;

Miller, AB ;

Miller, LR ;

Payne, JA ;

Ray, JA ;

Samano, V ;

Shewchuk, LM ;

Tavares, FX ;

Wells-Knecht, KJ ;

Willard, DH ;

Wright, LL ;

Zhou, HQQ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (15) :3540-3546

[6] Acyclic cyanamide-based inhibitors of cathepsin K [J].

Barrett, DG ;

Deaton, DN ;

Hassell, AM ;

McFadyen, RB ;

Miller, AB ;

Miller, LR ;

Payne, JA ;

Shewchuk, LM ;

Willard, DH ;

Wright, LL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (12) :3039-3043

[7] A structural screening approach to ketoamide-based inhibitors of cathepsin K [J].

Barrett, DG ;

Catalano, JG ;

Deaton, DN ;

Long, ST ;

McFadyen, RB ;

Miller, AB ;

Miller, LR ;

Wells-Knecht, KJ ;

Wright, LL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (09) :2209-2213

[8] Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1′, P1, and/or P3 substitutions [J].

Barrett, DG ;

Catalano, JG ;

Deaton, DN ;

Hassell, AM ;

Long, ST ;

Miller, AB ;

Miller, LR ;

Shewchuk, LM ;

Wells-Knecht, KJ ;

Willard, DH ;

Wright, LL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (19) :4897-4902

[9] Orally bioavailable small molecule ketoamide-based inhibitors of cathepsin K [J].

Barrett, DG ;

Catalano, JG ;

Deaton, DN ;

Long, ST ;

Miller, LR ;

Tavares, FX ;

Wells-Knecht, KJ ;

Wright, LL ;

Zhou, HQQ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (10) :2543-2546

[10] Assessing the performance of OMEGA with respect to retrieving bioactive conformations [J].

Boström, J ;

Greenwood, JR ;

Gottfries, J .

JOURNAL OF MOLECULAR GRAPHICS & MODELLING, 2003, 21 (05) :449-462