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

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页码：304 / 318

页数：15

相关论文

共 47 条

[1] Crystallographic and thermodynamic analysis of the binding of S-octylglutathione to the Tyr 7 to phe mutant of glutathione S-transferase from Schistosoma japonicum [J].

Andújar-Sánchez, M ;

Smith, AW ;

Clemente-Jimenez, JM ;

Rodriguez-Vico, F ;

Heras-Vazquez, FJL ;

Jara-Pérez, V ;

Cámara-Artigas, A .

BIOCHEMISTRY, 2005, 44 (04) :1174-1183

[2] A monomer form of the glutathione S-transferase Y7F mutant from Schistosoma japonicum at acidic pH [J].

Andújar-Sánchez, M ;

Clemente-Jimenez, JM ;

Rodriguez-Vico, F ;

Las Heras-Vazquez, FJ ;

Jara-Pérez, V ;

Cámara-Artigas, A .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 314 (01) :6-10

[3] Glutathione-doxorubicin conjugate expresses potent cytotoxicity by suppression of glutathione S-transferase activity: comparison between doxorubicin-sensitive and -resistant rat hepatoma cells [J].

Asakura, T ;

Ohkawa, K ;

Takahashi, N ;

Takada, K ;

Inoue, T ;

Yokoyama, S .

BRITISH JOURNAL OF CANCER, 1997, 76 (10) :1333-1337

[4] Identification of the nonsubstrate steroid binding site of rat liver glutathione S-transferase, isozyme 1-1, by the steroid affinity label, 3 beta-(iodoacetoxy)dehydroisoandrosterone [J].

Barycki, JJ ;

Colman, RF .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1997, 345 (01) :16-31

[5] Schistosomiasis: from risk assessment to control [J].

Bergquist, NR .

TRENDS IN PARASITOLOGY, 2002, 18 (07) :309-314

[6] GLUTATHIONE TRANSFERASE IN HELMINTHS [J].

BROPHY, PM ;

BARRETT, J .

PARASITOLOGY, 1990, 100 :345-349

[7] Mass spectrometry and immobilized enzymes for the screening of inhibitor libraries [J].

Cancilla, MT ;

Leavell, MD ;

Chow, J ;

Leary, JA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (22) :12008-12013

[8] Characterization of the electrophile binding site and substrate binding mode of the 26-kDa glutathione S-transferase from Schistosoma japonicum [J].

Cardoso, RMF ;

Daniels, DS ;

Bruns, CM ;

Tainer, JA .

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2003, 51 (01) :137-146

[9] Praziquantel: is there real resistance and are there alternatives? [J].

Cioli, D .

CURRENT OPINION IN INFECTIOUS DISEASES, 2000, 13 (06) :659-663

[10] Chemical-induced nephrotoxicity mediated by glutathione S-conjugate formation [J].

Dekant, W .

TOXICOLOGY LETTERS, 2001, 124 (1-3) :21-36

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