Pharmacophore fingerprinting. 1. Application to QSAR and focused library design

A new method of rapid pharmacophore fingerprinting (PharmPrint method) has been developed. A basis set of 10 549 three-point pharmacophores has been c onstructed by enumerating several distance ranges and pharmacophoric featur es. Software has been developed to assign pharmacophoric types to atoms in chemical structures, generate multiple conformations, and construct the bin ary fingerprint according to the pharmacophores that result. The fingerprin t is used as a descriptor for developing a quantitative structure-activity relationship (QSAR) model using partial least squares. An example is given using sets of ligands for the estrogen receptor (ER). The result is compare d with previously published results on the same data to show the superiorit y of a full 3D, conformationally flexible approach. The QSAR model can be r eadily interpreted in structural/chemical tens. Further examples are given using binary activity data and some of our novel in-house compounds, which show the value of the model when crossing compound classes.