Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization.
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Sanders WJ, Nienaber VL, Lerner CG, McCall JO, Merrick SM, Swanson SJ, Harlan JE, Stoll VS, Stamper GF, Betz SF, Condroski KR, Meadows RP, Severin JM, Walter KA, Magdalinos P, Jakob CG, Wagner R, Beutel BA
Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization.
J Med Chem. 2004 Mar 25;47(7):1709-18.
- PubMed ID
- 15027862 [ View in PubMed]
- Abstract
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.