Fragonomics, Eh?

Edward Zartler ("Teddy Z" of the Practical Fragments blog) has a short piece in the latest ACS Medicinal Chemistry Letters on fragment-based drug discovery. He applies the term "fragonomics" to the field (more on this in a moment), and provides a really useful overview of how it should work.

One of his big points is that fragment work isn't so much about using smaller-than-usual molecules, as it is using molecules that make only good interactions with the target.. It's just that smaller molecules are far more likely to achieve that - a larger one will have some really strong interactions, along with some things that actually hurt the binding. You can start with something large and hack pieces of it off, but that's often a difficult process (and you can't always recapitulate the binding mode, either). But if you have a smaller piece that only makes a positive interaction or two, then you can build out from that, tiptoeing around the various landmines as you go. That's the concept of "ligand efficiency", without using a single equation.

He also emphasizes that having a simpler molecule to work on means that the SAR can be tested and expanded quickly, often without anyone hitting the lab bench at all. You can order things up from the vendors or raid your own screening collection for close analogs. This delays the entry of the medicinal chemists to the project, which (considering that their time is always in demand) is a feature to be happy about.

The article ends up by saying...

Source: In the Pipeline - August 21, 2014 Category: Chemists Tags: Drug Assays Source Type: blogs