In drug design, scientists have been seeking guidelines to prioritize compounds with a high likelihood of permeability (e.g. entry into mammalian cells, entry into gram-negative pathogens, blood-brain-barrier penetration, and passage across epithelial barriers). Medicinal chemists relate permeability to the polarity of the compounds which is commonly represented by in silico descriptors such as the number of hydrogen-bond acceptors (HBA) and donors (HBD) or the topological polar surface area. Iterative design cycles for new compounds are often guided by these descriptors and the HBA and HBD counts are part of the famous rule of 5. It is however well known that some compounds have good permeability beyond the space delineated by these rules with a classic example being cyclosporine. One aspect not taken into account by the existing descriptors is the presence of intramolecular hydrogen bonds (IAHB) which can reduce the exposed polarity of a molecule and thereby enhance or maintain permeability. Our work focuses on developing a predictive model for IAHB in small molecules in order to improve calculated descriptors by taking their effect on polarity into account. The model is based on crystallographic data from the Cambridge Structural Database (CSD) using geometrical criteria to define the IAHB.

Improving drug design by predicting exposed polarity

253rd National Meeting (2017)

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