Thousands of chemical starting points for antimalarial lead identification

被引：772

作者：

Gamo, Francisco-Javier ^{[1
]}

Sanz, Laura M. ^{[1
]}

Vidal, Jaume ^{[1
]}

de Cozar, Cristina ^{[1
]}

Alvarez, Emilio ^{[1
]}

Lavandera, Jose-Luis ^{[1
]}

Vanderwall, Dana E. ^{[2
]}

Green, Darren V. S. ^{[3
]}

Kumar, Vinod ^{[4
]}

Hasan, Samiul ^{[4
]}

Brown, James R. ^{[4
]}

Peishoff, Catherine E. ^{[5
]}

Cardon, Lon R. ^{[6
]}

Garcia-Bustos, Jose F. ^{[1
]}

机构：

[1] GlaxoSmithKline, Tres Cantos 28760, Spain

[2] GlaxoSmithKline, Computat & Struct Chem, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline, Computat & Struct Chem, Med Res Ctr, Stevenage SG1 2NY, Herts, England

[4] GlaxoSmithKline, Quantitat Sci, Computat Biol, Collegeville, PA 19426 USA

[5] GlaxoSmithKline, Computat & Struct Chem, Collegeville, PA 19426 USA

[6] GlaxoSmithKline, Quantitat Sci, King Of Prussia, PA 19406 USA

来源：

NATURE | 2010年 / 465卷 / 7296期

关键词：

PLASMODIUM-FALCIPARUM; MALARIA; DRUGS; SENSITIVITY; DISCOVERY; EFFICACY; KINOME; GENOME;

D O I：

10.1038/nature09107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 mu M concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.

引用

页码：305 / U56

页数：8

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