Designing Combinatorial Libraries for Efficient Screening

Half a century ago, the term “drug discovery” conjured images of adventures into the jungle, beneath the sea, and atop mountains in search of frogs, sponges, lichens, or any unstudied life form that, ground up, might exhibit inhibitory effects toward a major human disease. More romantic and exciting science cannot be, to those of us too young to have participated in the “old” drug discovery paradigm, and perhaps also not more laborious, unpredictable, and frightening when included in a business plan. Combinatorial chemistry and high-throughput screening evolved to fill the need for a more systematic approach to discovery, in which miniaturization and automation were applied, as in traditional manufacturing processes, to reduce costs and cycle times. But to the contrary, the cost associated with producing clinical candidates seems to have actually risen with the application of these technologies (1 –3 ).