Modeling the evolution of drug resistance in malaria.
J Comput Aided Mol Des
; 26(12): 1343-53, 2012 Dec.
Article
em En
| MEDLINE
| ID: mdl-23179493
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Pirimetamina
/
Resistência a Medicamentos
/
Malária Falciparum
/
Evolução Molecular
/
Di-Hidropteroato Sintase
/
Antimaláricos
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article