title: First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Daines
authors.forename: Israil
authors.initials: I
authors.lastname: Pendrak
authors.forename: Kelvin
authors.initials: K
authors.lastname: Sham
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Van Aller
authors.forename: Alex K
authors.initials: AK
authors.lastname: Konstantinidis
authors.forename: John T
authors.initials: JT
authors.lastname: Lonsdale
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.forename: Martin
authors.initials: M
authors.lastname: Brandt
authors.forename: Sanjay S
authors.initials: SS
authors.lastname: Khandekar
authors.forename: Carol
authors.initials: C
authors.lastname: Silverman
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase