Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery
Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery
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将构象平衡与构象体特异性亲脂性联系起来：药物发现的新机遇
DOI：
10.1002/ange.202114862
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发表时间：
2021
影响因子：
--
通讯作者：
Linclau B
中科院分区：
文献类型：
--
作者：
Linclau B
高效的药物发现是基于在优化生物活性和化合物特性(如亲脂性)方面的协同努力，并以反映这两个方面的效率指标为指导。虽然构象-活性关系和配基构象控制是已知的提高生物活性的策略，但使用构象特异性脂亲性(LOGP)的探索要少得多。在这里，我们展示了如何从宏观的logP值和单个物种在水和辛醇中的平衡常数的知识中获得构象特定的对数值。这一点以氟化酰胺旋转体为例，通过集成旋转体19F核磁共振信号作为一种简单、直接的方法来获得对数值。强调了logP和logP优化之间的区别，为药物发现中的亲脂性控制提供了一种新的途径。
Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation–activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer‐specific lipophilicities (logp) is much less explored. Here we show how conformer‐specific logpvalues can be obtained from knowledge of the macroscopic logPvalue, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer19F NMR signals as a facile, direct method to obtain logpvalues. The difference between logpand logPoptimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.