Homology modeling of wild type and pyrimethamine/cycloguanil-cross resistant mutant type Plasmodium falciparum dihydrofolate reductase. A model for antimalarial chemotherapy resistance.
We propose a low-resolution model for both the wild type and the pyrimethamine (Pyr)/cycloguanil (Cyc) cross-resistant mutant type Plasmodium falciparum DHFR (PfDHFR), based on homology modeling using chicken liver DHFR as a template. The built models contain five alpha-helices, eight beta-sheets, eight tight turns and several loops. The Ramachandran plot for the models shows 95.3 and 100% of the amino acid residues in the favorable regions for the whole enzymes and for the active sites, respectively. Furthermore, we made a preliminary analysis of the complexes Pyr/Cyc-wild DHFR and Pyr/Cyc-mutant DHFR in order to explain the probable mechanism of resistance. Our results show that the steric factor may be the main structural cause of P. falciparum resistance toward antifolate drugs.
Santos-Filho
O A
OA
Departamento de Química, Instituto Militar de Engenharia, Praça General Tibúrcio 80, Praia Vermelha 22290-270, Rio de Janeiro, Brazil.
de Alencastro
R B
RB
Figueroa-Villar
J D
JD
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001665:Binding Sites; D002645:Chickens; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D002727:Proguanil; D011739:Pyrimethamine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*
D000962:Antimalarials; D005493:Folic Acid Antagonists; D014227:Triazines; C026009:cycloguanil; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D011739:Pyrimethamine