Challenges in the Medicinal Chemical Optimization of Binding Kinetics

This chapter describes the key considerations and challenges to optimizing binding kinetics. The challenges relate both to our ability to measure on and off rates in a manner that informs optimization but also in our limited molecular understanding of the processes that govern on and off rates. The effects of individual molecular interactions and bulk physicochemical properties are discussed. A number of significant case studies from the literature are described, which serve to highlight these principles. These examples also illustrate that empirical optimization of residence time is possible if given adequate attention during optimization and that some of the principles discussed may have general applicability.