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Malaria remains the global public health problem due to the reemergence of drug resistance. There is an urgent need for development of new antimalarial candidates which are effective against resistant malaria parasite. This systematic review evaluates the published research studies that applied in silico modeling during the discovery process of antimalarial drugs. Literature searches were conducted using PubMed, EBSCO, EMBASE, and Web of Science to identify the relevant articles using the search terms "Malaria" "In silico model", "Computer-based drug design", "Antimalarial drug", and "Drug discovery". Only the articles published in English between 2008 and May 2015 were included in the analysis. A total of 17 relevant articles met the search criteria. Most articles are studies specific to Plasmodium falciparum targets; 3 and 1 articles, respectively involve target for P. vivax and liver stage of Plasmodium. Both structure-based and ligand-based approaches were applied to obtain lead antimalarial candidates. Two articles also assessed absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Confirmation of activity of the candidate leads by in vitro and/or in vivo assays were reported in some studies. Homology modelling, molecular docking, 2D-or 3D-QSAR and pharmacophore modeling are commonly applied methods. One study used de novo synthesis for lead identification and one study applied phylogenetic analysis for target identification/validation.

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Abstract. CYP2A6, CYP2B6, and UGT1A9 genetic polymorphisms and treatment response after a three-day course of artesunate-mefloquine was investigated in 71 Burmese patients with uncomplicated Plasmodium falciparum malaria. Results provide evidence for the possible link between CYP2A6 and CYP2B6 polymorphisms and plasma concentrations of artesunate/dihydroartemisinin and treatment response. In one patient who had the CYP2A6*1A/*4C genotype (decreased enzyme activity), plasma concentration of artesunate at one hour appeared to be higher, and the concentration of dihydroartemisinin was lower than for those carrying other genotypes (415 versus 320 ng/mL). The proportion of patients with adequate clinical and parasitologic response who had the CYP2B6*9/*9 genotype (mutant genotype) was significantly lower compared with those with late parasitologic failure (14.0% versus 19.0%). Confirmation through a larger study in various malaria-endemic areas is required before a definite conclusion on the role of genetic polymorphisms of these drugmetabolizing enzymes on treatment response after artesunate-based combination therapy can be made.

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