The Power of Two
Finding strong binders from dual-display barcoded chemical libraries
The goal of chemical libraries is to contain enough molecules that even targets with uncommon binding sites can find the rare compound that binds with high affinity. Rather than synthesizing hundreds of thousands of molecules, a Swiss group has played a different numbers game by designing a dual-display system that employs two sub-libraries of hundreds of molecules attached to the 5' or 3' ends of complementary DNA strands. The system can be used to select molecule pairs that bind two sites on a target with higher affinity together than either molecule alone, but it doesn't solve the problem of how to link the two binders to build a therapeutic agent.
"The idea of taking two 100-micromolar compounds and getting a 10-nanomolar compound by linking them together is tremendously exciting," said Derek Lowe, a medicinal chemist and author of a widely read blog on drug research...