Measuring Diversity: Experimental Design of Combinatorial Libraries for Drug Discovery

Martin EJ, Blaney JM, Siani MA, Spellmeyer DC, Wong AK, Moos WH

Chiron Corp.,4560 Horton Street, Emeryville, California 94608-2916 and Daylight Chemical Information Systems, Inc., 441 Greg Ave., Sante Fe New Mexico 87501

Screening synthetic combinatorial libraries, such as mixtures of oligo(N-substituted)glycines, facilitates rapid drug lead discovery and optimiaztion by vastly increasing the number of candidate molecules made and tested. Discovery efficeincy and productivity can be further improved by using experimental design to maximize molecular diversity for a given library size or to bias the library with key features for a specific receptor. We describe new methods to quantify molecular diversity using descriptors that characterize lipophilicity, shape and branching, chemical functionality, and specific binding features. Experimental design methods select sets of side chains that are diverse in these properties, and "flower plots" allow the diversity to be graphically compared. We also quantify the overall diversity accesible to different families of combinatorial chemistry.

Journal of Medicinal Chemistry ,38,1995,1432-1436