Pharmacophore fingerprinting. 2. Application to primary library design

A methodology for pharmacophore fingerprinting (PharmPrint), previously described in the context of QSAR, has been used to address the issues involved in primary library design. A subset of the MDDR (MDDR9104) has been used to define a reference set of bioactive molecules. A statistic has been devised to measure the discriminating power of molecular descriptors using the target class assignments for this set, for which the PharmPrint fingerprint outperformed other descriptors. A principal components analysis (PCA) of the fingerprints for the MDDR9104 produces a low dimensional representation within which molecular properties and other libraries can be visualized and explored. PCA calculations on subsets of classes show that this space is robust to the addition of new classes, suggesting that pharmacophoric space is finite and rapidly converging. We demonstrate the application of the PharmPrint methodology to the analysis and design of virtual combinatorial libraries using common scaffolds and building blocks.