Design of potent inhibitors for Schistosoma japonica glutathione S-transferase

被引：21

作者：

Jao, SC

Chen, J

Yang, K

Li, WS ^{[1
]}

机构：

[1] Acad Sinica, Inst Chem, Taipei 11529, Taiwan

[2] Natl Cent Univ, Dept Chem, Chungli 32054, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2006年 / 14卷 / 02期

关键词：

drug design; molecular modeling; epiandrosterone; Schistosoma japonica glutathione S-transferase; inhibitors;

D O I：

10.1016/j.bmc.2005.07.077

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We implemented both structure-based drug design and the concept of polyvalency to discover a series of potent and unsymmetrical Schistosoma japonicum glutathione S-transferase (SjGST) inhibitors 10-12. This strategy achieved not only an excellent enhancement (10- to 490-fold) in the inhibitory potency, compared to the monofunctional analogues 1-5, but was also an effective modification by selecting a hydrophobic moiety with a flexible linker. The designed compounds with a low micromolar hit demonstrate special values in refining the new generation of SjGST inhibitors. The stoichiometry of the binding is one inhibitor molecule per SjGST monomer via isothermal titration calorimetric measurement. (c) 2005 Elsevier Ltd. All rights reserved.

引用

收藏

页码：304 / 318

页数：15

相关论文

共 47 条

[11] Crystal structure of human glutathione S-transferase A3-3 and mechanistic implications for its high steroid isomerase activity [J].

Gu, YJ ;

Guo, JX ;

Pal, A ;

Pan, SS ;

Zimniak, P ;

Singh, SV ;

Ji, XH .

BIOCHEMISTRY, 2004, 43 (50) :15673-15679

[12] Detection of large pKα perturbations of an inhibitor and a catalytic group at an enzyme active site, a mechanistic basis for catalytic power of many enzymes [J].

Ha, NC ;

Kim, MS ;

Lee, WT ;

Choi, KY ;

Oh, BH .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (52) :41100-41106

[13]

HABIG WH, 1974, J BIOL CHEM, V249, P7130

[14]

HALL A, 1989, CANCER RES, V49, P6265

[15] Glutathione S-transferase of the malarial parasite Plasmodium falciparum:: Characterization of a potential drug target [J].

Harwaldt, P ;

Rahlfs, S ;

Becker, K .

BIOLOGICAL CHEMISTRY, 2002, 383 (05) :821-830

[16] The glutathione S-Transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance [J].

Hayes, JD ;

Pulford, DJ .

CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1995, 30 (06) :445-600

[17] Evolutionary and biomedical implications of a Schistosoma japonicum complementary DNA resource [J].

Hu, W ;

Yan, Q ;

Shen, DK ;

Liu, F ;

Zhu, ZD ;

Song, HD ;

Xu, XR ;

Wang, ZJ ;

Rong, YP ;

Zeng, LC ;

Wu, J ;

Zhang, X ;

Wang, JJ ;

Xu, XN ;

Wang, SY ;

Fu, G ;

Zhang, XL ;

Wang, ZQ ;

Brindley, PJ ;

McManus, DP ;

Xue, CL ;

Feng, Z ;

Chen, Z ;

Han, ZG .

NATURE GENETICS, 2003, 35 (02) :139-147

[18] Sulfur and selenium: The role of oxidation state in protein structure and function [J].

Jacob, C ;

Giles, GL ;

Giles, NM ;

Sies, H .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2003, 42 (39) :4742-4758

[19] Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones [J].

Johansson, AS ;

Mannervik, B .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (35) :33061-33065

[20]

Kaplan W, 1997, PROTEIN SCI, V6, P399

← 1 2 3 4 5 →