Discovery of Potent Inhibitors of Dihydroneopterin Aldolase Using CrystaLEAD High-Throughput X-ray Crystallographic Screening and Structure-Directed Lead Optimization
| العنوان: | Discovery of Potent Inhibitors of Dihydroneopterin Aldolase Using CrystaLEAD High-Throughput X-ray Crystallographic Screening and Structure-Directed Lead Optimization |
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| المؤلفون: | Stephen F. Betz, Kevin Ronald Condroski, John E. Harlan, Bruce A. Beutel, Jean M. Severin, Sean M. Merrick, Vicki L. Nienaber, Susan J. Swanson, Rolf Wagner, Vincent S. Stoll, Karl A. Walter, J. Owen McCall, Peter Magdalinos, Claude G. Lerner, William J. Sanders, Geoffrey F. Stamper, Clarissa G. Jakob, Robert P. Meadows |
| المصدر: | Journal of Medicinal Chemistry. 47:1709-1718 |
| بيانات النشر: | American Chemical Society (ACS), 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Models, Molecular, Guanine, Databases, Factual, Molecular model, Stereochemistry, Dihydroneopterin aldolase, Crystallography, X-Ray, Benzoates, Neopterin, Structure-Activity Relationship, Drug Discovery, Structure–activity relationship, Enzyme Inhibitors, Aldehyde-Lyases, chemistry.chemical_classification, Binding Sites, Molecular Structure, biology, Chemistry, Aldolase A, Active site, Triazoles, Lyase, Crystallography, Pyrimidines, Enzyme, Purines, Enzyme inhibitor, biology.protein, Molecular Medicine |
| الوصف: | Potent inhibitors of 7,8-dihydroneopterin aldolase (DHNA; EC 4.1.2.25) have been discovered using CrystaLEAD X-ray crystallographic high-throughput screening followed by structure-directed optimization. Screening of a 10 000 compound random library provided several low affinity leads and their corresponding X-ray crystal structures bound to the enzyme. The presence of a common structural feature in each of the leads suggested a strategy for the construction of a directed library of approximately 1000 compounds that were screened for inhibitory activity in a traditional enzyme assay. Several lead compounds with IC(50) values of about 1 microM against DHNA were identified, and crystal structures of their enzyme-bound complexes were obtained by cocrystallization. Structure-directed optimization of one of the leads thus identified afforded potent inhibitors with submicromolar IC(50) values. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm030497y |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a9dbe31b69612381bbc2a0bdaca49a2d https://doi.org/10.1021/jm030497y |
| رقم الانضمام: | edsair.doi.dedup.....a9dbe31b69612381bbc2a0bdaca49a2d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/jm030497y |