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首页> 外文期刊>Journal of Medicinal Chemistry >Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase
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Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase

机译：合成的和晶体学研究针对炭疽芽孢杆菌二氢叶酸还原酶的新型抑制剂系列。

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摘要

Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da. to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 angstrom resolution. The structure reveals several features that can be exploited for further development of this lead series.
机译：炭疽杆菌是炭疽的病原体，具有重大的生物防御危险。批准的治疗方法的严重局限性和耐药性的产生，迫切需要针对这种生物的新型治疗剂。由于缺乏抗二氢叶酸还原酶的能力，已知炭疽芽孢杆菌对临床使用的抗叶酸甲氧苄啶不敏感。在这里，我们描述了以扩展的甲氧苄啶类支架为特征的炭疽芽孢杆菌二氢叶酸还原酶抑制剂的新型先导系列。最好的铅化合物仅添加22 Da。的分子量比甲氧苄氨嘧啶高82倍。测定了在NADPH存在下与炭疽芽孢杆菌二氢叶酸还原酶结合的该前导化合物的X射线晶体结构至2.25埃分辨率。结构揭示了可用于进一步开发该潜在客户系列的几个功能。

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