New frontiers in applied biophysics: advancing drug discovery using single-molecule microscopy

Since the last event of a drug interacting with its target occurs one molecule at a time, it stands to reason that the ability to observe the structures, time courses, and interactions of individual molecules will be important to optimizing drug properties. While bulk measurements provide ensemble-average properties of molecules, important information is often obscured from view. Recently, single-molecule methods have emerged in the field of drug discovery and development to fill in these gaps. Benefits of single-molecule resolution include reduced sample consumption, higher detection sensitivity, and enabling direct visualization of multi-step molecular interactions. In this review, we attempt to bridge the gap between the fields of biophysics and drug discovery to increase the interaction between these fields and drive progress together. First, we give a brief overview of the drug discovery process, which is intended for the biophysics community. Then, we review a series of single-molecule techniques, including both well-established and newly emerging technologies, highlighting key drug discovery insights and possible future applications of each technique. Looking forward, we are inspired to see the advent and application of single-molecule methods and biophysical approaches to drive real-world impacts in drug discovery by providing crucial and complementary information to bulk measurements. Looking ahead, we are excited about the widespread impact that bringing the fields of biophysics and drug discovery together will have on myriad classes of emerging medicines and energizing the required research.