RESUMEN
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.
Asunto(s)
Antimaláricos/farmacología , Antagonistas del Ácido Fólico/farmacología , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Pirimetamina/farmacología , Tetrahidrofolato Deshidrogenasa/metabolismo , Triazinas/farmacología , Secuencia de Aminoácidos , Animales , Sitios de Unión , Pollos , Resistencia a Medicamentos , Humanos , Hígado/enzimología , Hígado/patología , Malaria/parasitología , Modelos Biológicos , Modelos Moleculares , Datos de Secuencia Molecular , ProguanilRESUMEN
Interaction studies using hydrogen NMR spin-lattice relaxation time measurements of a series of five antiparasitic guanyl hydrazones with SDS and cetyl trimethylammonium bromide micelles are used as a simple model for the interaction of these compounds with the cell membrane of Trypanosoma cruzi. The results show that the activity of the compounds is related to their capacity to selectively interact with anionic micelles, which reinforces the hypothesis that the mechanism of action of these compounds is related to their selective interaction with the negatively charged parasite membrane.