Thousands of chemical starting points for antimalarial lead identification

20 May 2010

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

Nature

DOI: 10.1038/nature09107

Published in Nature, GSK, in collaboration with MMV, describe the screening of 2,000,000 compounds against P. falciparum. This output has led to multiple series being prosecuted in Hit-to-Lead and Lead Optimization. The two most advanced series show excellent in vivo activity and are advanced Lead Optimization projects within the MMV portfolio. The data and structures of the confirmed hits have been made available in the ChEMBL-NTD online database.

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.Wescreened 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 mM 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.

The full article can be viewed on Nature's website.