title: Novel inhibitors of beta-ketoacyl-ACP reductase from Escherichia coli.
abstract: Bacterial beta-ketoacyl-[acyl carrier protein] (beta-ketoacyl-ACP) reductase (FabG) is a highly conserved and ubiquitously expressed enzyme of the fatty-acid biosynthetic pathway of prokaryotic organisms that catalyzes NADPH-dependent reduction of beta-ketoacyl-ACP intermediates. Therefore, FabG represents an appealing target for the development of new antimicrobial agents. A number of trans-cinnamic acid derivatives were designed and screened for inhibitory activities against FabG from Escherichia coli. These inhibited FabG enzymatic activity with IC(50) values in the microM range, and were used as templates for the subsequent diversification of the chemotype. Introduction of an electron-withdrawing 4-cyano group to the phenol substituent showed improved inhibition over the non-substituted compound. The benzo-[1,3]-dioxol moiety also appeared to be essential for inhibitory activity of trans-cinnamic acid derivatives against FabG from E. coli. To explain the possible binding position, the best inhibitor from the present study was docked in the active site of FabG. The results for the best scoring conformers chosen by the docking programme revealed that cinnamic acid derivatives can be accommodated in the substrate-binding region of the active site, above the nicotinamide moiety of the NADPH cofactor. Additionally, a phage-displayed library of random linear 15-mer peptides was screened against FabG, to identify ligands with the common PPLTXY motif.
authors.affiliation: Drug Discovery, Lek Pharmaceuticals dd, Ljubljana, Slovenia. katja.kristan@sandoz.com
authors.forename: Katja
authors.initials: K
authors.lastname: Kristan
authors.forename: Tomaz
authors.initials: T
authors.lastname: Bratkovic
authors.forename: Matej
authors.initials: M
authors.lastname: Sova
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Andrej
authors.initials: A
authors.lastname: Prezelj
authors.forename: Uros
authors.initials: U
authors.lastname: Urleb
mesh_terms: D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D020134:Catalytic Domain; D002934:Cinnamates / Q000737:chemistry; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D002934:Cinnamates; D017931:DNA Primers; D004791:Enzyme Inhibitors; D010455:Peptides; C029010:cinnamic acid; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase