First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling

Robert A Daines; Israil Pendrak; Kelvin Sham; Glenn S Van Aller; Alex K Konstantinidis; John T Lonsdale; Cheryl A Janson; Xiayang Qiu; Martin Brandt; Sanjay S Khandekar; Carol Silverman; Martha S Head

doi:10.1021/jm025571b

First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling

J Med Chem. 2003 Jan 2;46(1):5-8. doi: 10.1021/jm025571b.

Authors

Robert A Daines¹, Israil Pendrak, Kelvin Sham, Glenn S Van Aller, Alex K Konstantinidis, John T Lonsdale, Cheryl A Janson, Xiayang Qiu, Martin Brandt, Sanjay S Khandekar, Carol Silverman, Martha S Head

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA.

PMID: 12502353
DOI: 10.1021/jm025571b

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.

MeSH terms

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / chemistry*
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Indoles / chemical synthesis*
Indoles / chemistry
Models, Molecular
Molecular Structure
Streptococcus pneumoniae / chemistry

Substances

Enzyme Inhibitors
Indoles
3-ketoacyl-acyl carrier protein synthase III
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase

Associated data

PDB/1MZS