Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase
Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase
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DOI：
10.1021/jm900861d
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发表时间：
2010-01-14
影响因子：
7.3
通讯作者：
Lee, Richard E.
中科院分区：
文献类型：
--
作者：
Hevener, Kirk E.;Yun, Mi-Kyung;Lee, Richard E.
二氢蝶呤酸合酶(DHPS)是细菌叶酸合成的关键酶，也是磺胺类抗菌药物的靶标。磺胺类药物的耐药性和毒性已导致其临床应用的减少。与磺胺类药物靶向的对氨基苯甲酸(PABA)结合部位相反，与DHP的蝶呤结合部位结合的化合物有望绕过磺胺耐药性。为了识别这样的抑制剂并绘制蝶呤结合口袋的图谱，我们使用炭疽芽孢杆菌DHPS进行了虚拟筛选、合成和结构研究。已鉴定了几个具有抑制活性的化合物，并确定了晶体结构，表明这些化合物是如何与蝶呤结合的。结构研究确定了关键的结合元件，并已被用于生成基于结构-活性的药效团图谱，该图谱将促进专门针对蝶呤位点的下一代或DHPS抑制剂的开发。
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, arc 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 or DHPS inhibitors which specifically target the pterin site.