Fragment-based inhibitor discovery against β-lactamase.
Fragment-based inhibitor discovery against β-lactamase.
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DOI：
10.4155/fmc.14.10
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发表时间：
2014-03
影响因子：
4.2
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Nichols DA;Renslo AR;Chen Y
β-内酰胺酶的产生是革兰氏阴性细菌病原体对抗β-内酰胺类抗生素（如青霉素类、头孢菌素类和碳青霉烯类）的主要耐药机制之一。迫切需要开发新的β-内酰胺酶抑制剂以响应不断发展的具有扩展的β-内酰胺水解活性谱的β-内酰胺酶。尽管传统的高通量筛选已被证明对丝氨酸β-内酰胺酶无效，但基于片段的方法已成功用于鉴定新的化学物质，这反过来又揭示了丝氨酸和金属β-内酰胺酶活性位点可能的特异性分子相互作用。在这篇综述中，我们总结了该领域的最新进展，特别是：通过基于片段的筛选鉴定新的抑制剂化学型;使用片段-蛋白质结构来了解结合热点的关键特征并为改进的先导物的设计提供信息;使用基于片段的方法开发β-内酰胺酶抑制剂的经验教训和新前景。
The production of β-lactamase is one of the primary resistance mechanisms used by Gram-negative bacterial pathogens to counter β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems. There is an urgent need to develop novel β-lactamase inhibitors in response to ever evolving β-lactamases possessing an expanded spectrum of β-lactam hydrolyzing activity. Whereas traditional high-throughput screening has proven ineffective against serine β-lactamases, fragment-based approaches have been successfully employed to identify novel chemical matter, which in turn has revealed much about the specific molecular interactions possible in the active site of serine and metallo β-lactamases. In this review, we summarize recent progress in the field, particularly: the identification of novel inhibitor chemotypes through fragment-based screening; the use of fragment-protein structures to understand key features of binding hot spots and inform the design of improved leads; lessons learned and new prospects for β-lactamase inhibitor development using fragment-based approaches.
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作者：
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抑制c杆菌属的C类β-内酰胺酶：对有效抑制剂设计的见解。
影响因子：
2.9
作者：
Drawz, Sarah M.;Babic, Maja;Bethel, Christopher R.;Taracila, Magda;Distler, Anne M.;Ori, Claudia;Caselli, Emilia;Prati, Fabio;Bonomo, Robert A.
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