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首页> 外文期刊>Biochemistry >Rational optimization of drug-target residence time: Insights from inhibitor binding to the staphylococcus aureus FabI enzyme-product complex
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Rational optimization of drug-target residence time: Insights from inhibitor binding to the staphylococcus aureus FabI enzyme-product complex

机译：合理优化药物靶标停留时间：抑制剂与金黄色葡萄球菌FabI酶-产物复合物结合的见解

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Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for a series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) - an important target for the development of new anti-staphylococcal drugs - as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient, and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Because of its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 h. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme.
机译：药物靶向动力学最近已成为药物发现过程中一个特别重要的方面。特别地，延长的药物靶标停留时间可以在开放的体内系统中赋予增强的功效和选择性。但是，缺乏一系列同类化合物的准确动力学和结构数据，阻碍了脱附率降低的抑制剂的合理设计。因此，我们选择了金黄色葡萄球菌烯酰-ACP还原酶（saFabI）（开发新的抗葡萄球菌药物的重要目标）作为模型系统，以在结构上合理化和优化药物靶标停留时间。使用我们新的，有效的和广泛适用的机械知识的动力学方法，我们获得了一系列20种二苯醚与9种saFabI抑制剂晶体结构相辅相成的saFabI抑制的完整表征。我们确定了所研究的saFabI二苯醚抑制剂的亲和力与它们对应的停留时间之间有很强的相关性，可以在结构上进行合理化。由于其与酶的良好相互作用，我们最有效的化合物的停留时间超过10小时。另外，我们发现通过仔细考虑催化作用可预测的修饰可以显着提高该系统中的亲和力和停留时间。我们的研究为研究和延长药物靶向动力学提供了一个蓝图，并且可能有助于合理设计针对必需saFabI酶的长效抑制剂。

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