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.