Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization.
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.
Sanders
William J
WJ
Infectious Disease Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA. will.sanders@abbott.com
Nienaber
Vicki L
VL
Lerner
Claude G
CG
McCall
J Owen
JO
Merrick
Sean M
SM
Swanson
Susan J
SJ
Harlan
John E
JE
Stoll
Vincent S
VS
Stamper
Geoffrey F
GF
Betz
Stephen F
SF
Condroski
Kevin R
KR
Meadows
Robert P
RP
Severin
Jean M
JM
Walter
Karl A
KA
Magdalinos
Peter
P
Jakob
Clarissa G
CG
Wagner
Rolf
R
Beutel
Bruce A
BA
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*
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