Details

Autor(en) / Beteiligte

• Sanders, William J
• Nienaber, Vicki L
• Lerner, Claude G
• McCall, J. Owen
• Merrick, Sean M
• Swanson, Susan J
• Harlan, John E
• Stoll, Vincent S
• Stamper, Geoffrey F
• Betz, Stephen F
• Condroski, Kevin R
• Meadows, Robert P
• Severin, Jean M
• Walter, Karl A
• Magdalinos, Peter
• Jakob, Clarissa G
• Wagner, Rolf
• Beutel, Bruce A

Titel

Discovery of Potent Inhibitors of Dihydroneopterin Aldolase Using CrystaLEAD High-Throughput X-ray Crystallographic Screening and Structure-Directed Lead Optimization

Ist Teil von

• Journal of medicinal chemistry, 2004-03, Vol.47 (7), p.1709-1718

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 IC50 values of about 1 μM 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 IC50 values.