Prioritization of Molecular Targets for Antimalarial Drug Discovery

Abstract

There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in Plasmodium species. Given the high attrition rate and high cost of drug discovery, it is important to select the targets most likely to deliver progressible drug candidates. In this paper, we describe the criteria that we consider important for selecting targets for antimalarial drug discovery. We describe the analysis of a number of drug targets in the Malaria Drug Accelerator (MalDA) pipeline, which has allowed us to prioritize targets that are ready to enter the drug discovery process. This selection process has also highlighted where additional data are required to inform target progression or deprioritization of other targets. Finally, we comment on how additional drug targets may be identified.

Keywords: Plasmodium; drug discovery; malaria; molecular targets.

Figure 1

Geographical location of MalDA consortium members. MalDA, with its state-of-the-art Plasmodium-adapted technology platforms in bioinformatics, chemo-informatics, chemo-proteomics, genetic manipulation, metabolomics, in vivo resistance evaluation, and medicinal chemistry expertise, is at the forefront of the antimalarial drug discovery process by providing tools to accelerate the finding of new starting points for drug discovery (www.malariaDA.org).

Figure 2

Current MalDA target portfolio

Figure 3

Structures of tool compounds (see text for references to each structure)

Figure 4

(A) Analysis of the P. falciparum genome categorizing targets according to their predicted essentiality, druggability, and the presence of mammalian orthologs. The number of proteins in each category is shown in parentheses. (B) Analysis of high value targets, according to tool compounds, the presence of mammalian orthologs, and proof of concept in humans. The number of proteins in each category is shown in parentheses. Where there is only one protein in a category, it is stated explicitly. Most MalDA targets fall into the light blue or violet regions.