In a landmark paper, Topliss [1] described a decision tree approach to guide a medicinal chemist to the most potent analogue by rational analysis of the activity order observed so far. One of the decision trees involved substituted phenyl rings. After synthesizing and measuring the potency of the phenyl and 4-chlorophenyl derivatives, subsequent molecules to synthesize and test were suggested based on the observed potency order of those already measured. Topliss derived the tree based on a consideration of the sigma, pi and steric effects of the substituents. Now that large amounts of published activity data are available from databases such as ChEMBL, it is possible to compare the suggestions of Topliss with those obtained by analyzing activity data across many different scaffolds and targets. We present a Topliss-like decision tree derived from activity data in ChEMBL [2] and compare its predictions to those of the original tree. An advantage of our approach is that it is possible to apply it to any situation for which sufficient data is available, for example, a tree based on data just from kinases. Furthermore, it is possible to inspect the data on which predictions are based. [1] Topliss, J. G. J. Med. Chem. 1972 , 15, 1006-1011.[2] O'Boyle, N.M.; Bostr�m, J.; Sayle, R.A.; Gill, A. J. Med. Chem. 2014 , In press. DOI:10.1021/jm500022q

Revising the Topliss decision tree based on 30 years of medicinal chemistry literature

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.