Tipparaju, S.K., Muench, S.P., Mui, E.J. et al. (10 more authors) (2010) Identification and Development of Novel Inhibitors of Toxoplasma gondii Enoyl Reductase. Journal of Medicinal Chemistry, 53 (17). pp. 6287-6300. ISSN 0022-2623
Abstract
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 MIC90s ≤ 6 μM without toxicity to host cells, three compounds have IC90s < 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 Å. 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2010 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
Keywords: | CARRIER PROTEIN REDUCTASE; FATTY-ACID SYNTHESIS; X-RAY-STRUCTURE; PLASMODIUM-FALCIPARUM; ACP REDUCTASE; ESCHERICHIA-COLI; ANTIBACTERIAL AGENTS; ANTIMICROBIAL TARGETS; TRICLOSAN INHIBITION; OCULAR TOXOPLASMOSIS |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Molecular Biology and Biotechnology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 27 Feb 2017 13:12 |
Last Modified: | 06 Apr 2018 01:44 |
Published Version: | https://doi.org/10.1021/jm9017724 |
Status: | Published |
Publisher: | American Chemical Society |
Refereed: | Yes |
Identification Number: | 10.1021/jm9017724 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:110883 |