Allosteric drugs: New principles and design approaches

Focusing on an important biomedical implication of allostery – design of allosteric drugs, we describe characteristics of allosteric sites, effectors, and their modes of actions distinguishing them from the orthosteric counterparts and calling for new principles and protocols in the quests for allosteric drugs. We show the importance of considering both binding affinity and allosteric signaling in establishing the structure–activity relationships (SARs) toward design of allosteric effectors, arguing that pairs of allosteric sites and their effector ligands – the site-effector pairs – should be generated and adjusted simultaneously in the framework of what we call directed design protocol. Key ideas and approaches for designing allosteric effectors including reverse perturbation, targeted and agnostic analysis are also discussed here. Several promising computational approaches are highlighted, along with the need for and potential advantages of utilizing generative models to facilitate discovery/design of new allosteric drugs.