Log P as a tool in intramolecular hydrogen bond considerations

Abstract

Intramolecular hydrogen bonding (IMHB) considerations are gaining relevance in drug discovery and a molecular descriptor which can predict very early the capacity of a compound to form IMHB is needed to speed up the optimization process of drug candidates. Although log P_oct is largely used for optimization purposes, in this paper we firstly use the Block Relevance (BR) analysis to theoretically show how log P_oct is not a convenient choice to assess IMHB properties of candidates. Then we discuss the limits of log P_oct and introduce Δlog P_oct-tol, i.e. the difference between log P_oct and log P_tol (the logarithm of the partition coefficient in the toluene/water system). Finally, we provided some examples also including bRo5 protease inhibitors, to clarify how to interpret Δlog P_oct-tol values.