Tipparaju, Suresh K and Muench, Stephen P and Mui, Ernest J and Ruzheinikov, Sergey N and Lu, Jeffrey Z. and Hutson, Samuel L and Kirisits, Michael J. and Prigge, Sean T. and Roberts, Craig and Henriquez, Fiona L and Kozikowski, Alan P and Rice, David W and McLeod, Rima L (2010) Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. Journal of Medicinal Chemistry, 53 (17). pp. 6287-6300.Full text not available in this repository. (Request a copy from the Strathclyde author)
Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s <or = 6 microM without toxicity to host cells, three compounds have IC(90)s <45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.
|Keywords:||animals, cultured cells, coccidiostats, crystallography X-Ray, cytochrome P-450 enzyme system, enoyl-(acyl-carrier-protein) reductase (NADH), fibroblasts, humans, mice, microbial sensitivity tests, liver microsomes, molecular models, molecular structure, nitriles, nitrobenzenes, phenyl ethers, pyridines, structure-activity relationship, toxoplasma, toxoplasmosis, Pharmacy and materia medica, Drug Discovery, Molecular Medicine|
|Subjects:||Medicine > Pharmacy and materia medica|
|Department:||Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences|
|Depositing user:||Pure Administrator|
|Date Deposited:||28 Sep 2011 13:22|
|Last modified:||20 May 2016 03:37|