Abstract
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.
Highlights
Bruno Linclau,* Zhong Wang, Benjamin Jeffries, Jérôme Graton, Rodrigo J
A concerted effort towards bioactivity optimization and lipophilicity control is regarded as the best strategy for successful drug discovery.[5]
We report here how conformer equilibrium constants K in octanol and water are intricately linked to microscopic lipophilicities (Figure 1C), which allows logp values to be obtained indirectly
Summary
Bruno Linclau,* Zhong Wang, Benjamin Jeffries, Jérôme Graton, Rodrigo J. For 3D structures, quantum chemistry calculations can predict logP values, as these provide solvation energy differences between water and octanol for each conformer determining the conformer equilibria between, as well as within, the phases.
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