Structural studies of pterin-based inhibitors of dihydropteroate synthase.
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.
Hevener
Kirk E
KE
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Avenue, Room 327 Johnson Building, Memphis, Tennessee 38163, USA.
Yun
Mi-Kyung
MK
Qi
Jianjun
J
Kerr
Iain D
ID
Babaoglu
Kerim
K
Hurdle
Julian G
JG
Balakrishna
Kanya
K
White
Stephen W
SW
Lee
Richard E
RE
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
D004791:Enzyme Inhibitors; D011622:Pterins; D004094:Dihydropteroate Synthase