Finding the sweet spot: the role of nature and nurture in medicinal chemistry
Finding the sweet spot: the role of nature and nurture in medicinal chemistry
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DOI：
10.1038/nrd3701
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发表时间：
2012-05-01
影响因子：
120.1
通讯作者：
Keserue, Gyoergy M.
中科院分区：
文献类型：
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作者：
Hann, Michael M.;Keserue, Gyoergy M.
鉴于其在小分子药物发现中的核心地位，药物化学在解决药物研究和开发中众所周知的生产力挑战方面发挥着重要作用。近年来，对成功和失败的发现化合物和候选药物的广泛分析提高了我们对物理化学性质在药物损耗中的作用的理解。基于在药物化学项目中寻找“最佳点”的明确挑战，我们建议通过首先确定具有适当“性质”的化学起点，然后在先导物优化过程中严格“培养”它们的组合来实现这一目标。在这里，我们讨论药物化学实践的科学，战略，组织和文化方面的考虑，目的是促进更有效地利用已知的东西，以及更广泛地了解追求次优化合物的风险。
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.