Allostery: The Good, the Bad, and the Ugly

With the advent of functional screening, more allosteric molecules are being discovered and developed as possible therapeutic enti-ties. Allosteric proteins are unique because of two specific proper-ties: 1) separate binding sites for allosteric modulators and guests and 2) mandatory alteration of receptor conformation upon binding of allosteric modulators. For G protein-coupled receptors, these properties produce many beneficial effects on pharmacologic sys-tems that are described here. Allosteric discovery campaigns also bring with them added considerations that must be addressed for the endeavor to be successful, and these are described herein as well. SIGNIFICANCE STATEMENT Recent years have seen the increasing presence of allosteric molecules as possible therapeutic drug candidates. The sci-entific procedures to characterize these are unique and re-quire special techniques, so it is imperative that scientists understand the new concepts involved in allosteric function. This review examines the reasons why allosteric molecules should be considered as new drug entities and the techni-ques required to optimize the discovery process for allosteric molecules.