Table 1.
Selection of promising drug targets for biochemical screens
| Enzyme name (PlasmoDB ID) | Essentiality | Druggability score* | Genome-wide percentile ranking** |
|---|---|---|---|
| Adenylosuccinate synthase (PF13_0287) | Part of purine salvage pathway, which should be essential because Plasmodium cannot synthesize purines de novo [63]. | 0.8 | 99.5% |
| Choline kinase (PF14_0020) | Chemical validation of the Kennedy pathway for phosphatidylcholine synthesis is suggested by the work of Henri Vial [64]. | 0.6 | 97.9% |
| dUTPase (PF11_0282) | dUTPase is most likely essential because it prevents the buildup of dUTP and makes dUMP for dTTP synthesis [47]. | 0.6 | 99.8% |
| Farnesyl pyrophosphate synthase (PVX_092040) | Since protein farnesyltransferase is a valid drug target in Plasmodium [51], FPPS should be as well because it supplies the substrate for PFT. A recent paper reported an ability to predict cell-killing activity from bisphosphonates’ inhibition of FPPS [54]. | 0.8 | 99.3% |
| Glutamate dehydrogenase (PF14_0164) | Thought to be a major source of NADPH for glutathione reductase, which is thought to be essential [65]. This is based in part on the fact that Plasmodium is “exposed to multiple oxidative stress due to its high metabolic rate, the degradation of heme and reactive oxygen species imposed by the host immune system” [66]. | 0.8 | 99.7% |
| Guanylate kinase (PVX_099895) | Based on metabolic maps, guanylate kinase appeared to be the only route by which Plasmodium can convert GMP to GDP or dGMP to dGDP. (A possible bypass is noted in the text.) Also, expression during liver stage [45] suggests importance in that stage. | 0.2 | 98.4% |
| N-myristoyltransferase (PF14_0127) | As argued by Gelb et al. [49], “Genetic studies have shown that the NMT gene is essential for viability in a range of species, including Drosophila melanogaster, S. cerevisiae and Candida albicans and Cryptococcus neoformans.” | 0.8 | 98.4% |
| OMP decarboxylase (PF10_0225) | Part of the de novo pyrimidine synthesis pathway, which should be essential in Plasmodium because it does not have a pyrimidine salvage pathway [63]. Also, chemical validation of the de novo pyrimidine pathway comes from studies of dihydroorotate dehydrogenase [46]. | N/A | 98.6% |
| S-adenosylhomocysteine hydrolase (PFE1050w) | Part of a methylation cycle whose blockage should be fatal [39]. | 0.8 | 99.9% |
Druggability scores were taken from TDRtargets.org. Scores range from 0.0 to 1.0, with 1.0 signifying maximum druggability and ~0.2 signifying an average score.
TDRtargets.org was used to perform a multiparameter weighted search, with points awarded for various features considered desirable in a potential drug target. Percentiles were then computed from a rank-order list of all genes in the Plasmodium genome. Points were awarded as follows: 8 points to each gene for each life cycle stage (merozoite, early and late ring, early and late schizont, and early and late trophozoite) in which their expression ranks in the top quintile (80th to 100th percentile) for a given erythrocyte life cycle stage; 4 points to each gene for each life cycle stage in which expression was in the 60th to 80th percentile; 50 points to each gene with genetic validation (according to manual curation of the literature); 35 points to each gene associated with one or more publications (according to an automated analysis of PubMed); 50 points to each gene with one or more associated crystal structures; 30 points to each gene for which there is a 3D structural model (ModBase); 25 points to each gene lacking an ortholog in humans; 20 points to each gene lacking a predicted transmembrane domain; 20 points to each gene coding for a protein less than 100 kilodaltons; 100 points to each gene coding for an enzyme; 40 points to each gene whose orthologs are essential in at least one model organism; and 30 points to each gene for which there is an activity assay available.