The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase

被引：56

作者：

Heikkilä, T

Thirumalairajan, S

Davies, M

Parsons, MR

McConkey, AG

Fishwick, CWG ^{[1
]}

Johnson, AP

机构：

[1] Univ Leeds, Sch Chem, Leeds LS2 9JT, W Yorkshire, England

[2] Univ Leeds, Sch Biochem & Microbiol, Leeds LS2 9JT, W Yorkshire, England

[3] Univ Leeds, Sch Biol, Leeds LS2 9JT, W Yorkshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 01期

基金：

英国惠康基金;

关键词：

medicinal chemistry; oxoreductases; inhibitors; molecular recognition; molecular modelling;

D O I：

10.1016/j.bmcl.2005.09.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The de novo molecular design program SPROUT has been applied to the X-ray crystal structures of Plasmodium and human dihydroorotate dehydrogenase, respectively. The resulting design templates were used to prepare a series of molecules which, in keeping with predictions, showed useful levels of species-selective enzyme inhibition. (c) 2005 Elsevier Ltd. All rights reserved.

引用

收藏

页码：88 / 92

页数：5

相关论文

共 20 条

[1] Spatial requirements of the antagonist binding site of the NK2 receptor [J].

Ali, MA ;

Bhogal, N ;

Fishwick, CWG ;

Findlay, JBC .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (06) :819-822

[2] High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase [J].

Baldwin, J ;

Michnoff, CH ;

Malmquist, NA ;

White, J ;

Roth, MG ;

Rathod, PK ;

Phillips, MA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (23) :21847-21853

[3] Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase [J].

Boa, AN ;

Canavan, SP ;

Hirst, PR ;

Ramsey, C ;

Stead, AMW ;

McConkey, GA .

BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (06) :1945-1967

[4]

CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099

[5] Helicobacter pylori-selective antibacterials based on inhibition of pyrimidine biosynthesis [J].

Copeland, RA ;

Marcinkeviciene, J ;

Haque, TS ;

Kopcho, LM ;

Jiang, WJ ;

Wang, K ;

Ecret, LD ;

Sizemore, C ;

Amsler, KA ;

Foster, L ;

Tadesse, S ;

Combs, AP ;

Stern, AM ;

Trainor, GL ;

Slee, A ;

Rogers, MJ ;

Hobbs, F .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (43) :33373-33378

[6] RECOMBINANT HUMAN DIHYDROOROTATE DEHYDROGENASE - EXPRESSION, PURIFICATION, AND CHARACTERIZATION OF A CATALYTICALLY FUNCTIONAL TRUNCATED ENZYME [J].

COPELAND, RA ;

DAVIS, JP ;

DOWLING, RL ;

LOMBARDO, D ;

MURPHY, KB ;

PATTERSON, TA .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1995, 323 (01) :79-86

[7] The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase [J].

Davis, JP ;

Cain, GA ;

Pitts, WJ ;

Magolda, RL ;

Copeland, RA .

BIOCHEMISTRY, 1996, 35 (04) :1270-1273

[8] Mechanism of action for leflunomide in rheumatoid arthritis [J].

Fox, RI ;

Herrmann, ML ;

Frangou, CG ;

Wahl, GM ;

Morris, RE ;

Strand, V ;

Kirschbaum, BJ .

CLINICAL IMMUNOLOGY, 1999, 93 (03) :198-208

[9] SPROUT - RECENT DEVELOPMENTS IN THE DE-NOVO DESIGN OF MOLECULES [J].

GILLET, VJ ;

NEWELL, W ;

MATA, P ;

MYATT, G ;

SIKE, S ;

ZSOLDOS, Z ;

JOHNSON, AP .

JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES, 1994, 34 (01) :207-217

[10] INHIBITION OF DIHYDROOROTATE DEHYDROGENASE BY THE IMMUNOSUPPRESSIVE AGENT LEFLUNOMIDE [J].

GREENE, S ;

WATANABE, K ;

BRAATZTRULSON, J ;

LOU, L .

BIOCHEMICAL PHARMACOLOGY, 1995, 50 (06) :861-867