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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DOI：
10.1002/anie.202114862
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发表时间：
2022-02-07
影响因子：
16.6
通讯作者：
Chiarparin, Elisabetta
中科院分区：
文献类型：
--
作者：
Linclau, Bruno;Wang, Zhong;Jeffries, Benjamin;Graton, Jerome;Carbajo, Rodrigo J.;Sinnaeve, Davy;Le Questel, Jean-Yves;Scott, James S.;Chiarparin, Elisabetta
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值以及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logP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logp值。强调了logP和logP优化之间的差异，为药物发现中的亲脂性控制提供了一种新的途径。捕捉构象：亲脂性(LogP)是一种分子性质，但它是单个构象的亲脂性的加权平均值。介绍了首次直接测量构象特定亲脂性的值，并介绍了一种合理优化候选药物亲脂性的新途径，其重点是改变水和辛醇中的构象平衡。
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 logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery. Catching conformations: Lipophilicity (logP) is a molecular property which is nevertheless the weighted average of the lipophilicities of the individual conformers. The first direct measurement of conformer‐specific lipophilicity values is presented, together with the introduction of a new avenue for rational lipophilicity optimization of drug candidates which is focused on modification of conformational equilibria in water and in octanol.
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作者：
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