title: Modeling the evolution of drug resistance in malaria.
abstract: Plasmodium falciparum, the causal agent of malaria, continues to evolve resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine. Here we study the amino acid replacements in dihydrofolate reductase (DHFR) that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH. The chain of amino acid replacements that has led to resistance can be inferred in a computer, leading to a broader understanding of the coevolution between the drug and target. This in silico approach suggests that only a small set of specific active site replacements in the proper order could have led to the resistant strains in the wild today. A similar approach can be used on any target of interest to anticipate likely pathways of future resistance for more effective drug development.
authors.affiliation: Southwestern College, Chula Vista, CA 91910, USA. dhecht@swccd.edu
authors.forename: David
authors.initials: D
authors.lastname: Hecht
authors.forename: Gary B
authors.initials: GB
authors.lastname: Fogel
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004094:Dihydropteroate Synthase / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance; D019143:Evolution, Molecular; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D011487:Protein Conformation; D011739:Pyrimethamine / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid
chemical_list: D000962:Antimalarials; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine