Structure-based approach to the development of potent and selective inhibitors of dihydrofolate reductase from cryptosporidium.

Article Details

Citation

Copy to clipboard

Bolstad DB, Bolstad ES, Frey KM, Wright DL, Anderson AC

Structure-based approach to the development of potent and selective inhibitors of dihydrofolate reductase from cryptosporidium.

J Med Chem. 2008 Nov 13;51(21):6839-52. doi: 10.1021/jm8009124. Epub 2008 Oct 4.

PubMed ID

18834108 [ View in PubMed

]

Abstract

Cryptosporidiosis is an emerging infectious disease that can be life-threatening in an immune-compromised individual and causes gastrointestinal distress lasting up to 2 weeks in an immune-competent individual. There are few therapeutics available for effectively treating this disease. We have been exploring dihydrofolate reductase (DHFR) as a potential target in Cryptosporidium. On the basis of the structure of the DHFR enzyme from C. hominis, we have developed a novel scaffold that led to the discovery of potent (38 nM) and efficient inhibitors of this enzyme. Recently, we have advanced these inhibitors to the next stage of development. Using the structures of both the protozoal and human enzymes, we have developed inhibitors with nanomolar potency (1.1 nM) against the pathogenic enzyme and high levels (1273-fold) of selectivity over the human enzyme.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
5-[(3R)-3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine	Dihydrofolate reductase	IC 50 (nM)	1360	7	25	Details