title: Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization.
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.
authors.affiliation: Infectious Disease Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA. will.sanders@abbott.com
authors.forename: William J
authors.initials: WJ
authors.lastname: Sanders
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Nienaber
authors.forename: Claude G
authors.initials: CG
authors.lastname: Lerner
authors.forename: J Owen
authors.initials: JO
authors.lastname: McCall
authors.forename: Sean M
authors.initials: SM
authors.lastname: Merrick
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Swanson
authors.forename: John E
authors.initials: JE
authors.lastname: Harlan
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Stamper
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Betz
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Condroski
authors.forename: Robert P
authors.initials: RP
authors.lastname: Meadows
authors.forename: Jean M
authors.initials: JM
authors.lastname: Severin
authors.forename: Karl A
authors.initials: KA
authors.lastname: Walter
authors.forename: Peter
authors.initials: P
authors.lastname: Magdalinos
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutel
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D019798:Neopterin / Q000737:chemistry*; D011687:Purines / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: C484863:3-(5-amino-7-hydroxy-(1,2,3)triazolo(4,5-d)pyrimidin-2-yl)benzoic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D011687:Purines; D011743:Pyrimidines; D014230:Triazoles; D006147:Guanine; D019798:Neopterin; D000446:Aldehyde-Lyases; C020044:dihydroneopterin aldolase