4DAI

Crystal structure of B. anthracis DHPS with compound 23

4DAI の概要

• エントリーDOI: 10.2210/pdb4dai/pdb
• 関連するPDBエントリー: 1TWS 4D8A 4D8Z 4D9P 4DAF 4DB7
• 分子名称: Dihydropteroate Synthase, (7-amino-4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazin-3-yl)acetic acid, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: paba, dhpp, pterin, dhps inhibitors, tim barrel, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Bacillus anthracis (anthrax)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67106.38

構造登録者

Hammoudeh, D.,Lee, R.E.,White, S.W. (登録日: 2012-01-12, 公開日: 2012-03-28, 最終更新日: 2023-09-13)

主引用文献

Zhao, Y.,Hammoudeh, D.,Yun, M.K.,Qi, J.,White, S.W.,Lee, R.E.
Structure-Based Design of Novel Pyrimido[4,5-c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity.
Chemmedchem, 7:861-870, 2012

PubMed Abstract: Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS is highly conserved and is distinct from the sulfonamide binding site. It therefore represents an attractive alternative target for the design of novel antibacterial agents. We previously carried out the structural characterization of a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise binding. With this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines were designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length are less apparent.

PubMed: 22416048
DOI: 10.1002/cmdc.201200049

実験手法

X-RAY DIFFRACTION (2.5 Å)