What’s going on with Bro5?

Some of you might wonder what this “Bro5” acronym stands for… Bro5, or “Beyond the rule of 5“, is meant to represent a vast chunk of chemistry space that is heavily populated by molecules that behave as drugs, yet do not satisfy the so-called Lipinski rule of 5 for drug-like properties. Here are the famous commandments from Lipinski:


As it typically happens, exceptions prove the rule. We don’t have to go very far: consider the case of taxol. This outlier is perfectly bioavailable, yet violates some of the Lipinski rules. The post-Lipinski period is characterized by trying to rationalize the behaviour of other outliers that emerge from drug discovery campaigns. More importantly, can we predict fairly large molecules with favourable oral bioavailability? When it comes to my lab’s research, the Bro5 considerations hit close to home as peptide macrocycles are among our favourite targets. The following paper, published several years ago by a team from Pfizer in the UK, contains a very nice discussion of Bro5. This manuscript also proves that it should be possible to rationally design orally bioavailable cyclic peptides. As you have seen in my older posts, formation of intramolecular hydrogen bonds is the main driver behind oral bioavailability of cyclic peptides. These weak interactions cooperatively shield polar functional groups and facilitate membrane permeability and intestinal absorption. One tantalizing question is whether or not it is possible to run simple predictions of intramolecular hydrogen bonds through modeling of the low energy gas phase macrocycle conformations. I have always thought that some of the coveted folded conformations of cyclic peptides might be fully predictable using such simple tools. The Pfizer work in MedChemComm supports this notion. So… Why painstakingly make a ton of macrocycles and screen them? Let’s make just one, baby…

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