The value of protein allostery in rational anticancer drug design: an update
Ruth Nussinov, Hyunbum Jang
Abstract
INTRODUCTION: Allosteric drugs are advantageous. However, they still face hurdles, including identification of allosteric sites that will effectively alter the active site. Current strategies largely focus on identifying pockets away from the active sites into which the allosteric ligand will dock and do not account for exactly how the active site is altered. Favorable allosteric inhibitors dock into sites that are nearby the active sites and follow nature, mimicking diverse allosteric regulation strategies. AREAS COVERED: The following article underscores the immense significance of allostery in drug design, describes current allosteric strategies, and especially offers a direction going forward. The article concludes with the authors' expert perspectives on the subject. EXPERT OPINION: To select a productive venue in allosteric inhibitor development, we should learn from nature. Currently, useful strategies follow this route. Consider, for example, the mechanisms exploited in relieving autoinhibition and in harnessing allosteric degraders. Mimicking compensatory, or rescue mutations may also fall into such a thesis, as can molecular glues that capture features of scaffolding proteins. Capturing nature and creatively tailoring its mimicry can continue to innovate allosteric drug discovery.