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Discovery of Novel Haloalkane Dehalogenase Inhibitors

机译：新型卤代烷脱卤酶抑制剂的发现

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Haloalkane dehalogenases (HLDs) have recently been discovered in a number of bacteria, including symbionts and pathogens of both plants and humans. However, the biological roles of HLDs in these organisms are unclear. The development of efficient HLD inhibitors serving as molecular probes to explore their function would represent an important step toward a better understanding of these interesting enzymes. Here we report the identification of inhibitors for this enzyme family using two different approaches. The first builds on the structures of the enzymes' known substrates and led to the discovery of less potent nonspecific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of an HLD from the human pathogen Mycobacterium tuberculosis H37Rv. The best inhibitor exhibited high specificity for the target structure, with an inhibition constant of 3 μM and a molecular architecture that clearly differs from those of all known HLD substrates. The new inhibitors will be used to study the natural functions of HLDs in bacteria, to probe their mechanisms, and to achieve their stabilization.
机译：最近在许多细菌中发现了卤代烷脱卤酶（HLD），包括植物和人类的共生菌和病原体。但是，尚不清楚HLD在这些生物中的生物学作用。开发用作分子探针以探索其功能的高效HLD抑制剂将代表朝着更好地了解这些有趣的酶迈出的重要一步。在这里，我们报告使用两种不同方法鉴定该酶家族的抑制剂。首先建立在酶已知底物的结构上，并导致发现效力较低的非特异性HLD抑制剂。第二种方法涉及从人类病原体结核分枝杆菌H37Rv中虚拟筛选15万种针对HLD晶体结构的潜在抑制剂。最好的抑制剂对目标结构表现出高特异性，抑制常数为3μM，分子结构明显不同于所有已知的HLD底物。新型抑制剂将用于研究HLD在细菌中的天然功能，以探究其机理，并实现其稳定性。

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