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 is largely used for optimization purposes, in this paper we firstly use the Block Relevance (BR) analysis to theoretically show how log P is not a convenient choice to assess IMHB properties of candidates. Then we discuss the limits of log P and introduce Δlog P, i.e. the difference between log P and log P (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 values.

Drug‐Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side‐Chain Lipophilicity

“…Previously we reported am etric called lipophilic permeability efficiency (LPE), which quantifies the efficiencyw ith which ac ompound achieves passive membrane permeability at agiven ALogP-defined lipophilicity. [15] LPE is derived from the difference between the experimental hydrocarbon-water partition coefficient, LogD(dd/w), which reflects amolecules net hydrogen bond acidity in its membrane-associated conformation, [16] and ALogP,w hich reflects ac ompoundsm inimum lipophilic character in the aqueous environment. [15] LPE, defined specifically by the equation LPE = logD(dd/ w)À1.06AlogP + 5.47, represents as caffoldsi ntrinsic membrane permeability by normalizing its membrane partitioning against its bulk lipophilicity.…”

Block relevance (BR) analysis and polarity descriptors in property-based drug design

“…4). In a previous study it was shown that nelfinavir has a larger propensity to form IMHBs than indinavir [30] and thus it was expected that Δlog P oct-tol , EPSA and log K w IAM of nelfinavir are smaller than the correspondent values determined for indinavir. This was verified for Δlog P oct-tol and log K w IAM but not for EPSA, which fails in ranking the polarity of the two protease inhibitors; probably because of the high and different number of HBA groups present in the structures.…”

The Development of New Molecules Having Antiemetic Activity Using Molecular Modeling

“…Using the molecular modeling and the application of the different theoretical methods we can calculate some properties: ξHOMO, ξLUMO, (Santos et al, 2019) the Dipole Moment (Lindic et al, 2019), Log (P) (Caron et al, 2018), the solubility... of three bioactive molecules.…”