Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

Abstract

This study demonstrates that logP oct-tol (difference between logPoctanol and logPtoluene) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates.We identified experimental protocols for acquiring reliable logP oct-tol values on a set of compounds representing IMHB motifs most prevalent in Medicinal Chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings.Furthermore, computational logP oct-tol values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB.The proposed interpretation method based on logP oct-tol data allowed categorization of the compounds into 2 groups -with high propensity to form IMHB and poor propensity or poor relevance of IMHB.The relative 1 H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme.4

The Block Relevance (BR) analysis supports the dominating effect of solutes hydrogen bond acidity on ΔlogPoct–tol

“…Our findings support the use of log P oct-tol as a molecular descriptor for the determination of the solutes HBD properties in drug discovery. In particular this study supports the recently published IMHB interpretation scheme (Shalaeva et al, 2013) that uses log P oct-tol as a tool to distinguish compounds based on their propensity to form IMHBs. …”

“…In fact a sample with strong propensity to form IMHB is expected to have lower exposure of HBD groups than its control. This results in a positive difference in log P oct-tol between the control and the sample, as predicted for compound belonging to category I by Shalaeva et al (Shalaeva et al, 2013).…”

“…In fact, it has been reported (Shalaeva et al, 2013) a small but systematic deviation in log P tol values when DMSO is present. Log P oct were also retrieved from literature, most from Abraham and coworkers (Abraham et al, 1994).…”

“…Very recently, Shalaeva and coworkers used log P oct-tol to distinguish compounds able to form IMHB (samples) from those with similar structure but unable to do that (controls) (Shalaeva et al, 2013). Here we prove that log P oct-tol mainly depends on the HBD properties of the solutes (see above) and thus support the application of log P oct-tol in the intramolecular hydrogen bonding interpretation scheme.…”

“…To overcome this difficulty, toluene was proposed to replace alkanes (Zissimov et al, 2002) (Shalaeva et al, 2013) in lipophilicity measurements. The general idea is that log P tol provides information similar to log P alk but it is easier to assess experimentally.…”