Objective

David C Swinney, Institute for Rare and Neglected Diseases Drug Discovery, Mountain View CA USA An important criterion for developing a new medicine is differentiation from standard of care. Differentiation can occur through increased efficacy, selectivity and/or safety resulting in an improved therapeutic index. Differentiated binding kinetics are a feature of the molecular mechanisms of drug action that increase selectivity and efficacy, and provide a molecular measure for optimization of these mechanisms. Binding kinetics are the molecular descriptors for binding/association and debinding/dissociation of a drug to its target. These kinetic rates can reveal understandings of molecular details of the dynamic processes of drug action beyond that disclosed by equilibrium constants (KI, KD), occupancy and IC50s. As such binding kinetics have the potential to provide additional information as to the molecular features that drive binding as well as the dynamic actions of drug binding that translate to selective drug action. Important to understanding the role of binding kinetics to occupancy and drug action is the equilibrium state of the system and the role of relative competing rates between drug binding/debinding and the rate of a competing physiologic processes such as the rates of channel open and closing, substrate degradation, receptor internalization. It is these competing rates that determine the specificity of the outcome in non-equilibrium physiological systems. In this talk I will present our experiences, strategies and learnings in using binding kinetics to differentiate the mechanism of drug action of clinical candidates.