I feel like I should dedicate several blog posts to hydrophobic effect. Many of us have developed an instinctive disdain for purely alkyl side chains in bioactive molecules. Seeing excessively greasy portions of natural products rarely elicits mainstream enthusiasm to prepare analogs whose structures contain primarily hydrophobic variations. Marvelous examples of truncated versions of natural products, in which excessively hydrophobic portions have been cut off, prove the point. But are there teachable nuances out there? I will turn to Klebe’s paper published in the J. Med. Chem. last year. The point of this study is that insufficiently protected water molecules covering protein surface should not be underestimated. You might recall me writing about the “underdehydrated” concept proposed by Fernandez in effort to explain Cyclosporine A’s capacity to protect hydrogen bonds from solvation. A somewhat similar situation takes place on the surface of a protein, where dynamic water networks respond differently to slight perturbations of hydrophobic groups that belong to an inhibitor. The structure below was found to be the best binder to thermolysin. If you look at the whole series, you will note that the heteroatom positions do not change and the only parameter that ensures variability is the subtle adjustment of the hydrophobic substituent. I think this is a marvelous case in defense of much maligned grease.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00998