Thousands of chemical starting points for antimalarial lead identification

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.

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Figure 1: Three-dimensional plot of some of the novel chemical diversity present in TCAMS.
Figure 2: Description of TCAMS and its target space.
Figure 3: Phylogenetic tree of combined human and P. falciparum kinomes.

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Acknowledgements

We thank S. Peregrina and S. Prats for technical assistance, and D. Jiménez-Alfaro for supplying compounds pre-dispensed in microtitre plates. We thank P. Vallance and R. Keenan for organising support for this work, R. Macarron and J. Luengo for developing the IFI index and getting the chemistry data ready for publication, together with J. M. Fiandor, S. Chakravorty and members of GSK’s Chemistry Council. J. Lewis, A. Clow, J. Overington and M. Davies were instrumental in the uploading and formatting of the data. We also thank N. Cammack, P. Sanseau and J. Burrows for critically commenting on the manuscript. The support and funding of Medicines for Malaria Venture is gratefully acknowledged.

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Authors

Contributions

F.-J.G. and J.F.G.-B. planned and designed the work. F.-J.G. supervised all experimental work and analysed the screening data, L.M.S., J.V., C.d.C. and E.A. performed the screening assays and contributed to data analysis. J.-L.L., D.E.V., D.V.S.G. and C.E.P. performed the cheminformatic analyses and wrote sections of the manuscript. V.K., S.H. and J.R.B. performed the bioinformatic analyses and J.R.B. contributed the relevant sections to the manuscript. L.R.C and J.F.G.-B integrated individual contributions and wrote the final manuscript.

Corresponding author

Correspondence to Jose F. Garcia-Bustos.

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The authors declare no competing financial interests.

Additional information

Chemical structures and data described have been deposited at EBI (http://www.ebi.ac.uk/chemblntd).

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-3 with legends and Supplementary Tables 3-5. (PDF 675 kb)

Supplementary Table 1

This table contains an annotated list of all positives from the P. falciparum screen. Structures are shown as "SMILES" codes. (XLS 3451 kb)

Supplementary Table 2

This table shows compounds in TCAMS with literature references on their mode of action. (XLS 437 kb)

Supplementary Data 1

The file contains the multiple kinase sequence alignment. This file was added on 2 June 2010. (TXT 173 kb)

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Gamo, F., Sanz, L., Vidal, J. et al. Thousands of chemical starting points for antimalarial lead identification. Nature 465, 305–310 (2010). https://doi.org/10.1038/nature09107

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