Molecular diversity: how we measure it? Has it lived up to its promise?

Molecular diversity needs to be considered when designing a screening set, whether a set of individual compounds or a combinatorial library. We have found that traditional substructure descriptors encode information relative to the biological properties of molecules. Of the methods tested, Ward's clustering is most effective. Combinatorial library design also requires consideration of the method of deconvolution and the combinatorial constraint. We have developed a genetic algorithm solution to this problem. Lastly, predicting affinity of molecules for a macromolecular target has been addressed with the use of a potential of mean force. There continues to be an opportunity for innovative computational approaches to solving problems in medicinal chemistry.