title: Structural studies of pterin-based inhibitors of dihydropteroate synthase.
abstract: Dihydropteroate synthase (DHPS) is a key enzyme in bacterial folate synthesis and the target of the sulfonamide class of antibacterials. Resistance and toxicities associated with sulfonamides have led to a decrease in their clinical use. Compounds that bind to the pterin binding site of DHPS, as opposed to the p-amino benzoic acid (pABA) binding site targeted by the sulfonamide agents, are anticipated to bypass sulfonamide resistance. To identify such inhibitors and map the pterin binding pocket, we have performed virtual screening, synthetic, and structural studies using Bacillus anthracis DHPS. Several compounds with inhibitory activity have been identified, and crystal structures have been determined that show how the compounds engage the pterin site. The structural studies identify the key binding elements and have been used to generate a structure-activity based pharmacophore map that will facilitate the development of the next generation of DHPS inhibitors which specifically target the pterin site.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Avenue, Room 327 Johnson Building, Memphis, Tennessee 38163, USA.
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Hevener
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Yun
authors.forename: Jianjun
authors.initials: J
authors.lastname: Qi
authors.forename: Iain D
authors.initials: ID
authors.lastname: Kerr
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.forename: Kanya
authors.initials: K
authors.lastname: Balakrishna
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011622:Pterins / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011622:Pterins; D004094:Dihydropteroate Synthase