Finding the sweet spot: the role of nature and nurture in medicinal chemistry

Given its position at the heart of small-molecule drug discovery, medicinal chemistry has an important role in tackling the well-known productivity challenges in pharmaceutical research and development. In recent years, extensive analyses of successful and failed discovery compounds and drug candidates have improved our understanding of the role of physicochemical properties in drug attrition. Based on the clarified challenges in finding the 'sweet spot' in medicinal chemistry programmes, we suggest that this goal can be achieved through a combination of first identifying chemical starting points with appropriate 'nature' and then rigorously 'nurturing' them during lead optimization. Here, we discuss scientific, strategic, organizational and cultural considerations for medicinal chemistry practices, with the aim of promoting more effective use of what is already known, as well as a wider appreciation of the risks of pursuing suboptimal compounds.