Chance Favors the Perplexed Mind: The Critical Role of Mechanistic Biochemistry in Drug Discovery

Scientific discoveries often start with an observation that does not quite make sense, within the framework of a well-established hypothesis. It is when researchers delve deeply to understand such perplexing data that established hypotheses are modified or replaced, and new and expanded knowledge of the system can be gained. This is often the case in the field of drug discovery. In this Perspective, case studies demonstrate how an understanding of perplexing data can lead to novel discoveries regarding the biological function of drug targets, or the mechanisms of compound-target interactions, that can ultimately result in new drugs entering the clinic. These case studies reinforce two interdependent themes: (1) that understanding the pathophysiological context in which drug targets function and the mechanistic details of drug-target interactions are critical to efficient and effective drug discovery and (2) that investing time and energy into following up on perplexing data can lead to novel discoveries that can drive the development of new and improved medicines.