Pharmacophore fingerprinting. 2. Application to primary library design

A methodology for pharmacophore fingerprinting (PharmPrint), previously des cribed 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 t o define a reference set of bioactive molecules. A statistic has been devis ed to measure the discriminating power of molecular descriptors using the t arget class assignments for this set, for which the PharmPrint fingerprint outperformed other descriptors. A principal components analysis (PCA) of th e fingerprints for the MDDR9104 produces a low dimensional representation w ithin which molecular properties and other libraries can be visualized and explored. PCA calculations on subsets of classes show that this space is ro bust to the addition of new classes, suggesting that pharmacophoric space i s finite and rapidly converging. We demonstrate the application of the Phar mPrint methodology to the analysis and design of virtual combinatorial libr aries using common scaffolds and building blocks.