Informative Library Design as an Efficient Strategy to Identify and Optimize Leads: Application to Cyclin-Dependent Kinase 2 Antagonists

The application of an informative, iterative library design strategy is presented for lead
identification and optimization. The computational algorithm underlying informative design
systematically uses data from both active and inactive compounds and maximizes the
information gained from subsequent design−synthesis−screening cycles. Retrospective analysis
of a released dataset of 17 550 compounds and corresponding cyclin-dependent kinase-2
activities showed that informative library design yields significant enrichments of active
compounds and efficiently discovers novel chemotypes in comparison with commonly used
diversity−similarity protocols.