Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase.
Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase.
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DOI：
10.1021/jm800776a
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发表时间：
2008-12-11
影响因子：
7.3
通讯作者：
Anderson AC
中科院分区：
文献类型：
--
作者：
Beierlein JM;Frey KM;Bolstad DB;Pelphrey PM;Joska TM;Smith AE;Priestley ND;Wright DL;Anderson AC
炭疽杆菌是炭疽病的病原体，具有重大的生物防御危险。批准的治疗剂的严重限制和耐药性的产生已经产生了对针对该生物体的新治疗剂的迫切需求。已知炭疽杆菌对临床上使用的抗叶酸剂甲氧苄啶不敏感，因为其对二氢叶酸还原酶缺乏效力。在此，我们描述了一种新的铅系列的B。炭疽二氢叶酸还原酶抑制剂，其特征在于延长的甲氧苄啶样支架。最好的先导化合物分子量仅增加22 Da，比甲氧苄啶有效82倍。与B结合的铅化合物的X射线晶体结构。在NADPH存在下测定炭疽二氢叶酸还原酶的分辨率为2.25 μ mol/L。该结构揭示了几个特点，可用于进一步开发该铅系列。
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 Å resolution. The structure reveals several features that can be exploited for further development of this lead series.
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影响因子：
4.9
作者：
Barrow, EW;Bourne, PC;Barrow, WW
通讯作者：
Barrow, WW
影响因子：
120.7
作者：
Neuhauser, MM;Weinstein, RA;Quinn, JP
通讯作者：
Quinn, JP
影响因子：
7.3
作者：
Rosowsky, A;Forsch, RA;Queener, SF
通讯作者：
Queener, SF
影响因子：
7.3
作者：
ROTH, B;AIG, E;RAUCKMAN, BS
通讯作者：
RAUCKMAN, BS
DOI：
10.1107/s1744309105002435
发表时间：
2005-03-01
影响因子：
0.9
作者：
Anderson, AC
通讯作者：
Anderson, AC