First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling.
The first cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor is reported. The inhibitor was obtained by rational modification of a high throughput screening lead with the aid of a S. pneumoniae FabH homology model. This homology model was used to design analogues that would have both high affinity for the enzyme and appropriate aqueous solubility to facilitate cocrystallization studies.
Daines
Robert A
RA
Department of Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA.
Pendrak
Israil
I
Sham
Kelvin
K
Van Aller
Glenn S
GS
Konstantinidis
Alex K
AK
Lonsdale
John T
JT
Janson
Cheryl A
CA
Qiu
Xiayang
X
Brandt
Martin
M
Khandekar
Sanjay S
SS
Silverman
Carol
C
Head
Martha S
MS
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013296:Streptococcus pneumoniae / Q000737:chemistry
D004791:Enzyme Inhibitors; D007211:Indoles; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase