Thousands of chemical starting points for antimalarial lead identification

Francisco-Javier Gamo, Laura M. Sanz, Jaume Vidal, Cristina de Cozar, Emilio Alvarez, Jose-Luis Lavandera, Dana E. Vanderwall, Darren V. S. Green, Vinod Kumar, Samiul Hasan, James R. Brown, Catherine E. Peishoff, Lon R. Cardon and Jose F. Garcia-Bustos ()
Additional contact information
Francisco-Javier Gamo: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
Laura M. Sanz: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
Jaume Vidal: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
Cristina de Cozar: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
Emilio Alvarez: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
Jose-Luis Lavandera: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
Dana E. Vanderwall: Computational and Structural Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, USA
Darren V. S. Green: Computational and Structural Chemistry, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, Stevenage SG1 2NY, UK
Vinod Kumar: Computational Biology, Quantitative Sciences, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Samiul Hasan: Computational Biology, Quantitative Sciences, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
James R. Brown: Computational Biology, Quantitative Sciences, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Catherine E. Peishoff: Computational and Structural Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Lon R. Cardon: Quantitative Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA
Jose F. Garcia-Bustos: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain

Nature, 2010, vol. 465, issue 7296, 305-310

Abstract: Abstract 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 µM 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.

Date: 2010
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DOI: 10.1038/nature09107

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