Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays.
Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays.
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DOI：
10.1016/j.bmc.2010.05.060
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发表时间：
2010-07-15
影响因子：
3.5
通讯作者：
Wiest, O.
中科院分区：
文献类型：
--
作者：
Henriksen, S. T.;Liu, J.;Estiu, G.;Oltvai, Z. N.;Wiest, O.
多重耐药金黄色葡萄球菌菌株的快速传播不仅需要新的治疗方案，还需要开发更快的方法来识别新的药物开发。如果能够达到足够的精度，计算方法的指数级增长速度使得在药物发现的早期阶段更广泛的使用具有吸引力。使用系统水平的方法进行的计算靶标鉴定表明组氨酸生物合成途径是抗S.金黄色。通过对接鉴定了该途径的潜在抑制剂，然后进行了整体重新评分，该整体重新评分足够准确，以证明通过全细胞测定法立即检测所鉴定的化合物是合理的，从而避免了耗时且通常困难的中间酶测定的需要。这种新的策略被证明为三个关键酶的S。金黄色葡萄球菌组氨酸生物合成途径，这被预测是必不可少的细菌生物量生产。对~106种化合物的库进行虚拟筛选，鉴定了该途径三种酶的49种潜在抑制剂。18个代表性化合物在3个S. aureus和两个E.大肠杆菌菌株的标准盘抑制测定。13个化合物是部分或全部S.金黄色葡萄球菌菌株，而14个化合物弱抑制生长在一个或两个E.大肠杆菌菌株。从快速虚拟筛选获得的高命中率证明了这种新策略对组氨酸生物合成途径的适用性。
The rapid spread on multi-drug resistant strains of Staphylococcus aureus requires not just novel treatment options, but the development of faster methods for the identification of new hits for drug development. The exponentially increasing speed of computational methods makes a more extensive use in the early stages of drug discovery attractive if sufficient accuracy can be achieved. Computational target identification using systems-level methods suggested the histidine biosynthesis pathway as an attractive target against S. aureus. Potential inhibitors for the pathway were identified through docking, followed by ensemble rescoring that is sufficiently accurate to justify immediate testing of the identified compounds by whole cell assays, avoiding the need for time-consuming and often difficult intermediary enzyme assays. This novel strategy is demonstrated for three key enzymes of the S. aureus histidine biosynthesis pathway, which is predicted to be essential for bacterial biomass productions. Virtual screening of a library of ~106 compounds identified 49 potential inhibitors of three enzymes of this pathway. 18 representative compounds were directly tested on three S. aureus-and two E. coli strains in standard disc inhibition assays. 13 compounds are inhibitors of some or all of the S. aureus strains, while 14 compounds weakly inhibit growth in one or both E. coli strains. The high hit rate obtained from a fast virtual screen demonstrates the applicability of this novel strategy to the histidine biosynthesis pathway.
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影响因子：
11.8
作者：
Klein E;Smith DL;Laxminarayan R
通讯作者：
Laxminarayan R
影响因子：
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作者：
Sievert, Dawn M.;Rudrik, James T.;Hageman, Jeffrey C.
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3.2
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作者：
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通讯作者：
Wilmanns, M
影响因子：
120.7
作者：
Klevens, R. Monina;Morrison, Melissa A.;Fridkin, Scott K.
通讯作者：
Fridkin, Scott K.