Lipophilic Efficiency as an Important Metric in Drug Design,Journal of Medicinal Chemistry

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Lipophilic Efficiency as an Important Metric in Drug Design
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-28 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00077
Ted W. Johnson ₁ , Rebecca A. Gallego ₁ , Martin P. Edwards ₁

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Lipophilic efficiency (LipE) is an important metric that has been increasingly applied in drug discovery medicinal chemistry lead optimization programs. In this Perspective, using literature drug discovery examples, we discuss the concept of rigorously applying LipE to guide medicinal chemistry lead optimization toward drug candidates with potential for superior in vivo efficacy and safety, especially when guided by physiochemical property-based optimization (PPBO). Also highlighted are examples of small structural modifications such as addition of single atoms, small functional groups, and cyclization that produce large increases in LipE. Understanding the factors that may contribute to LipE changes through analysis of ligand–protein crystal structures and using structure-based drug design (SBDD) to increase LipE by design is also discussed. Herein we advocate for use of LipE analysis coupled with PPBO and SBDD as an efficient mechanism for drug design.

中文翻译：

亲脂性效率是药物设计的重要指标

亲脂效率（LipE）是一项重要指标，已越来越多地应用于药物发现药物化学潜在客户优化程序中。在此“观点”中，我们将使用文献中的药物发现实例，讨论严格应用LipE来指导药物化学药物导联优化向具有更高的体内功效和安全性潜力的候选药物进行指导的概念，尤其是在基于物理化学性质的优化（PPBO）指导下。还强调了一些小的结构修饰的例子，例如添加单个原子，小的官能团和环化，这些修饰会导致LipE大量增加。还讨论了通过分析配体-蛋白质晶体结构并使用基于结构的药物设计（SBDD）通过设计增加LipE来了解可能引起LipE变化的因素。

更新日期：2018-03-28

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