Structural studies of pterin-based inhibitors of dihydropteroate synthase

Kirk Hevener, Mi Kyung Yun, Jianjun Qi, Iain D. Kerr, Kerim Babaoglu, Julian G. Hurdle, Kanya Balakrishna, Stephen W. White, Richard E. Lee

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)166-177
Number of pages12
JournalJournal of Medicinal Chemistry
Volume53
Issue number1
DOIs
StatePublished - Jan 28 2010

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Dihydropteroate Synthase
Pterins
Sulfonamides
Binding Sites
Bacillus anthracis
Benzoic Acid
Folic Acid
Enzymes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Hevener, K., Yun, M. K., Qi, J., Kerr, I. D., Babaoglu, K., Hurdle, J. G., ... Lee, R. E. (2010). Structural studies of pterin-based inhibitors of dihydropteroate synthase. Journal of Medicinal Chemistry, 53(1), 166-177. https://doi.org/10.1021/jm900861d

Structural studies of pterin-based inhibitors of dihydropteroate synthase. / Hevener, Kirk; Yun, Mi Kyung; Qi, Jianjun; Kerr, Iain D.; Babaoglu, Kerim; Hurdle, Julian G.; Balakrishna, Kanya; White, Stephen W.; Lee, Richard E.

In: Journal of Medicinal Chemistry, Vol. 53, No. 1, 28.01.2010, p. 166-177.

Research output: Contribution to journalArticle

Hevener, K, Yun, MK, Qi, J, Kerr, ID, Babaoglu, K, Hurdle, JG, Balakrishna, K, White, SW & Lee, RE 2010, 'Structural studies of pterin-based inhibitors of dihydropteroate synthase', Journal of Medicinal Chemistry, vol. 53, no. 1, pp. 166-177. https://doi.org/10.1021/jm900861d
Hevener, Kirk ; Yun, Mi Kyung ; Qi, Jianjun ; Kerr, Iain D. ; Babaoglu, Kerim ; Hurdle, Julian G. ; Balakrishna, Kanya ; White, Stephen W. ; Lee, Richard E. / Structural studies of pterin-based inhibitors of dihydropteroate synthase. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 1. pp. 166-177.
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