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

• Published in: Nature reviews. Drug discovery Vol. 11; no. 5; pp. 355 - 365
• Main Authors: Hann, Michael M., Keserü, György M.
• Format: Journal Article Book Review
• Language: English
• Published: London Nature Publishing Group UK 01-05-2012; Nature Publishing Group
• Subjects: 631/154/433; Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Chemical properties; Chemistry, Pharmaceutical - methods; Drug Design; Drug Discovery - methods; Drug Industry - organization & administration; Drugs; Efficiency, Organizational; Humans; Medicinal Chemistry; Molecular Medicine; opinion-2; Pharmaceutical chemistry; Pharmaceutical industry; Pharmaceutical Preparations - chemistry; Pharmacology/Toxicology; Product development; Research - organization & administration; Research Design; Risk
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd3701

Extensive analyses of successful and failed compounds in drug discovery and development have improved our understanding of the role of physicochemical properties in attrition. They have also clarified the difficulties in finding the 'sweet spot' in medicinal chemistry programmes. Hann and Keserü discuss scientific, strategic and cultural considerations for medicinal chemistry practices, with the aim of promoting more effective use of what is already known, and a wider appreciation of the risks of pursuing suboptimal compounds.
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.