Stereochemical Promiscuity in Artificial Transcriptional Activators

摘要

The prevailing paradigm driving the discovery of small molecules that perturb biological functions requires ligands of high affinity and specificity for a particular macromolecule. This paradigm is most effectively applied in cases where a single, well-defined binding site influences the function of the macromolecule. However, many biological processes are carried out by macromolecular complexes whose assembly and function are initiated through combinations of weaker interactions (micromolar K_Ds) with functionally redundant binding surfaces; in this way, a relatively small number of proteins can reside in more than one complex and/or participate in multiple functions. Small molecules that effectively regulate such systems will likely need to mimic the behavior of the endogenous participants.