针对炭疽芽孢杆菌二氢叶酸还原酶的新型抑制剂系列的合成与晶体学研究。
Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase.
作者信息
Beierlein Jennifer M, Frey Kathleen M, Bolstad David B, Pelphrey Phillip M, Joska Tammy M, Smith Adrienne E, Priestley Nigel D, Wright Dennis L, Anderson Amy C
机构信息
Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, Connecticut 06269, USA.
出版信息
J Med Chem. 2008 Dec 11;51(23):7532-40. doi: 10.1021/jm800776a.
Abstract
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 A resolution. The structure reveals several features that can be exploited for further development of this lead series.
摘要
炭疽杆菌是炭疽病的病原体，构成了重大的生物防御威胁。已批准的治疗方法存在严重局限性且产生了耐药性，因此迫切需要针对这种病原体的新型治疗药物。已知炭疽杆菌对临床使用的抗叶酸药物甲氧苄啶不敏感，因为它对二氢叶酸还原酶的效力不足。在此，我们描述了一系列新型的炭疽杆菌二氢叶酸还原酶抑制剂先导化合物，其特征是具有类似甲氧苄啶的扩展骨架。最佳先导化合物的分子量仅增加了22道尔顿，其效力比甲氧苄啶高82倍。在存在NADPH的情况下，该先导化合物与炭疽杆菌二氢叶酸还原酶结合的X射线晶体结构被解析到2.25埃的分辨率。该结构揭示了几个可用于进一步开发该先导化合物系列的特征。
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