Permeability into mammalian cells or gram-negative pathogens requires compounds to have chameleonic properties in terms of polarity. In recent years, interest in using intramolecular hydrogen bonds (IMHB) to modulate polarity of compounds has increased. Several publications have shown examples where permeability is increased by a transformation inducing an IMHB. In addition to providing an opportunity, these examples also raise many questions:<br/>Published pairs are isolated cases. Is the effect systematically positive? Are there counter examples? What are the parameters influencing this impact? How is efflux affected? Can we translate past examples into drug design principles?<br/>Our work focuses on answering these questions using in-house and ChEMBL permeability datasets (PAMPA, MDCK, Caco-2). We did a systematic search for pairs of analogues where one can form an IMHB and the other cannot using a novel fragment-based matched molecular pair (MMP) analysis workflow. Identification of IMHB is done based on patterns extracted from the Cambridge Structural Database and conformer generation through molecular modeling. We looked for most "ideal" MMPs where the transformation’s impact on other properties which play a role in permeability, such as pKa, is minimized. The impact of the IMHB on permeability in these extracted pairs is analyzed looking at various criteria including ring size, acceptor and donor types, flexibility, and predicted IMHB strength.

Intramolecular hydrogen bond impact on permeability via matched molecular pair analysis

255th National Meeting (2018)

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