Lipinski’s rule of five is probably one of the first principles taught to a medicinal chemist, as it defines the chemical space likely to yield a successful oral drug. However, in recent years some drugs have moved beyond traditional rule of five space in order to access alternative or challenging targets.
In this HOT paper David S. Millan and colleagues at Pfizer R&D explore the influence of intramolecular hydrogen bonding on the membrane permeability and bioavailability of some of these drugs. By determining the propensity of molecules to form intramolecular hydrogen bonds they are able to revise previous assumptions about where certain molecules sit in chemical space. They find that when hydrogen bonding is taken into account these drugs sit much closer to rule of five space – thereby explaining the successful absorption of drugs that otherwise violate rule of five principles.
To read more on this interesting new tool for predicting intramolecular hydrogen bonding, download the article which is currently free to access:
Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
Alexander Alex, David S. Millan, Manuel Perez, Florian Wakenhut and Gavin A. Whitlock
Med. Chem. Commun., 2011, Advance Article