Topliss Batchwise Schemes Reviewed in the Era of Open Data Reveal Significant Differences between Enzymes and Membrane Receptors

In 1977, John G. Topliss introduced
the Topliss Batchwise Scheme,
a straightforward nonmathematical procedure to assist medicinal chemists
in optimizing the substitution pattern of a phenyl ring. Despite its
long period of application, a thorough validation of this method has
been missing so far. Here, we address this issue by gathering 129
congeneric series from the ChEMBL database, suitable to retrospectively
assess the approach. Frequency analysis of Topliss’ schemes
showed that the π, Es, σ, and −σ scheme occurred
in 17, 20, 6, and 4 congeneric series, respectively. We observed a
significant difference of π scheme frequency in enzymes versus
membrane receptors, with 12 versus only 2 occurrences. Validation
of Topliss schemes in potency optimization showed a remarkable performance
increase after restricting the data set to analogue series tested
solely against enzymes. In this setting, the Es and the π scheme
were successful in 50% and 56% of the analogue series, respectively.