Modeling the evolution of drug resistance in Plasmodium falciparum DHFR

Plasmodium falciparum, the causal agent of malaria, has the ability to develop resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine rapidly. Here we apply in silico evolution to study and understand the evolutionary trajectories of the clinically relevant therapeutic anti-malaria target dihydrofolate reductase (DHFR). Amino acid replacements that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH are modeled as a co-evolutionary system. The preliminary results suggest a pathway of amino acid replacements that can arrive at a key amino acid replacement (S108N) believed to convey therapeutic resistance in vivo.