MOLECULAR DIVERSITY, BIOLOGICAL-ACTIVITY AND COMMON GROUND SHARED BY BOTH

This paper reviews some of the broad issues associated with the produc tion and screening of combinatorial libraries and proposes a guideline for optimizing the utility of combinatorial chemistry in drug discove ry. This guideline is based on the premise that our knowledge of how d iseases, biomolecular targets, and biologically active compound classe s interrelate can be used to define the most productive regions of mol ecular diversity space. Compound classes known to modulate function in various disease-related biomolecular target classes provide rich, val idated pharmacophores and should be given highest priority in the desi gn and construction of combinatorial libraries. This selection system is illustrated with alpha-ketoamide libraries for the inhibition of se rine and cysteine proteases and with oxindole libraries for the inhibi tion of protein kinases.