THE MEASUREMENT OF MOLECULAR DIVERSITY - A 3-DIMENSIONAL APPROACH

This paper describes a method for selecting a small, highly diverse su bset from a large pool of molecules. The method has been employed in t he design of combinatorial synthetic libraries for use in high-through put screening for pharmaceutical lead generation. It computes diversit y in terms of the main factors relevant to ligand-protein binding, nam ely the three-dimensional arrangement of steric bulk and of polar func tionalities and molecular entropy. The method was used to select a set of 20 carboxylates suitable for use as side-chain precursors in a pol yamine-based library. The method depends on estimates of various physi cal-chemical parameters involved in ligand-protein binding; experiment s examined the sensitivity of the method to these parameters. This pap er compares the diversity of randomly and rationally selected side-cha in sets; the results suggest that careful design of synthetic combinat orial libraries may increase their effectiveness several-fold.