17 November 2011

What do fragment hits look like?

Our last post highlighted a study showing that most of the best fragment hits loosely followed the Rule of 3, even though the library from which they were selected was not strictly Rule of 3 compliant. As it happens, Chris Swain at Cambridge MedChem Consulting has been tabulating fragment hits reported in the literature and has assembled a database of more than 280. Previously he has assessed the physicochemical properties of commercially available libraries; now, he’s analyzed the fragments that have actually been reported as hits and has published the results here.

For the most part the fragments conform to the Rule of 3. Size-wise most of them are truly fragments, with the majority having molecular weights less than 250 Da. Not surprisingly, they also tend to be fairly aromatic. Interestingly, roughly one third of the fragments are charged at physiological pH, with a pretty even split between acids and bases.

Of course, despite the overall Rule of 3 compliance, there are outliers in all the parameters, especially hydrogen-bond acceptors. So perhaps, to paraphrase Darren Begley channeling Bill Murray, the Rule of 3 should be renamed the Guideline of 3.


Pete said...

The NMR screening libraries with which I have been involved had the anion/cation/neutral ratio set to 1/1/4. This restriction was relaxed for the large (20k) generic fragment screening library and we ended up with more anions than cations. This was probably a consequence of anionic groups being structurally more diverse than cations.

The linked material doesn’t appear to state how the hydrogen bond acceptors were defined for the analysis. Also on one of the other pages on this website, the HBA and HBD restrictions of Ro3 are (as of 17-Nov-2011 since the error may get corrected in the future) stated as ‘<3’ which would make it Ro2.

Chris said...

I've corrected the typo on the Ro3.

The ChemAxon Acceptor definition used: an atom with a lone pair except for pyrrole-type aromatic N and the ester O (single bound)
Donor: an atom with H except for C atoms.
Apparently they are planning an option for setting the donor/acceptor definitions,