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.

Identification of an inhibitory pocket in falcilysin bound by chloroquine provides a new avenue for malaria drug development

“…In future studies it will be interesting to assess precisely to which level FLN-CQ binding contributes to the overall CQ MOA that is known to be intrinsically complex involving multiple molecular factors (see above). Nevertheless, results from this study indicate that the inhibitory CQ binding site on FLN could constitute a promising target for novel antimalaria drugs in the future and put FLN on the list of potential antimalarial drug targets for development programs that are currently ongoing around the world 51,52,[68][69][70] .…”

“…Knowledge of drug target(s) is imperative for the development of effective and safe antimalarials. Without knowing which part of the drug interacts with its target, chemical changes needed to improve the compound e cacy and safety are done in a trialerror manner 51,52 . Here, our MS-CETSA based screening approach successfully identi ed a number of potential drug binding partners of CQ and MK-4815 in P. falciparum, with FLN exerting the strongest thermal stabilization.…”

Discovery of Potent Plasmodium falciparum Protein Kinase 6 (PfPK6) Inhibitors with a Type II Inhibitor Pharmacophore

“…The different physiological environment of the target and its binding partners, which are not known, could also account for these differences. Target vulnerability could also play a role; if the parasite is able to survive with low levels of active enzyme, subtle changes in the potency or dissociation rates of inhibitors could affect their in cellulo activity 41 . Alternatively, these compounds could exert their cytotoxic effects through different targets with different mechanisms of action.…”

“…Our results demonstrate that 45 likely exerts its antiplasmodial activity through inhibition of multiple essential P. falciparum kinases. Polypharmacology has many advantages for antimalarial drug development, as it reduces the likelihood of resistance, provides opportunities for multistage intervention, and may inhibit enzymes of bypass pathways that would otherwise be able to compensate for inhibition of a single target 9,41 .…”

“…The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, concentrated onto Celite, and purified by flash chromatography (40-100% EtOAc in Hexanes on silica gel column) to afford 40 ( (41). To a solution of 4-((4-methylpiperazin-1-yl)methyl)aniline (55 mg, 0.27 mmol, 1.2 eq) in DMSO (1 mL) was added 1,1′carbonyldiimidazole (47 mg, 0.29 mmol, 1.3 eq).…”