Overview of Hit to Lead: The Medicinal Chemist's Role from HTS Retest to Lead Optimization Hand Off
Overview of Hit to Lead: The Medicinal Chemist's Role from HTS Retest to Lead Optimization Hand Off
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DOI：
10.1007/7355_2009_4
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发表时间：
2010-01-01
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影响因子：
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通讯作者：
Lipinski, Christopher A.
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文献类型：
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作者：
Lipinski, Christopher A.
药物化学家结合有机合成专业知识以及基于相关生物医学信息优化化学结构 - 活性关系（SAR）的能力，以实现项目目标。优化化学SAR的能力既包括较易解释的、通常由定量构效关系（QSAR）描述的逻辑逐步结构修饰，也包括更难解释的高阶模式识别实践。对于粗心的人来说，优化SAR充满陷阱。各种筛选类型的优缺点是什么？应该相信筛选数据吗？如何针对多种有时相互冲突的特性进行优化？哪些类型的化合物值得筛选？如何判断筛选命中化合物的质量？非常重要的是，药物发现是一项团队活动，药物化学家在其中起着关键的促进作用。鉴于良好的人际交往能力，药物化学家所受的训练足够广泛，使其能够在整个发现团队中进行合作互动。化学模式识别是药物化学家为药物发现贡献的独特技能。将化学结构与生物活性相关联以及改变化学结构从而使各种生物医学参数朝着期望方向改变的能力造就了成功的“药物猎人”。
A medicinal chemist combines organic synthesis expertise and the ability to optimize chemistry structure-activity relationships (SAR) based on relevant biomedical information so as to achieve project goals. The ability to optimize chemistry SAR consists of both the easier to explain logical stepwise structural modification that is often described by quantitative structure-activity relationships (QSAR) and the more difficult to explain exercise of high-order pattern recognition. Optimizing SAR is full of traps for the unwary. What are the pros and cons of various types of screens? Should one believe the screening data? How does one optimize against multiple sometimes conflicting properties? What types of compounds are worth screening? How does one judge the quality of a screening hit? Very importantly, drug discovery is a team exercise in which the medicinal chemist plays a key facilitating role. Given good interpersonal skills, the medicinal chemist's training is broad enough to enable cooperative interactions across the whole discovery team. Chemistry pattern recognition is the unique skill that the medicinal chemist contributes to drug discovery. The ability to relate chemistry structure to biological activity and to change chemistry structure so as to change a variety of biomedical parameters in a desired direction leads to the successful "drug hunter."