Oncology Medicinal Chemistry , Pfizer Inc. , 10770 Science Center Drive , La Jolla , California 92121 , United States.
J Med Chem. 2018 Aug 9;61(15):6401-6420. doi: 10.1021/acs.jmedchem.8b00077. Epub 2018 Apr 17.
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.
亲脂效率（LipE）是一个重要的指标，在药物发现和药物化学先导优化项目中得到了越来越多的应用。在本文中，我们通过文献药物发现实例讨论了严格应用 LipE 来指导药物化学先导优化，以获得具有潜在优异体内疗效和安全性的候选药物的概念，尤其是在基于理化性质优化（PPBO）的指导下。还强调了一些小的结构修饰的例子，如添加单个原子、小官能团和环化，这些修饰可以大大提高 LipE。通过分析配体-蛋白晶体结构来理解可能导致 LipE 变化的因素，并通过基于结构的药物设计（SBDD）来有意增加 LipE，也进行了讨论。在这里，我们提倡将 LipE 分析与 PPBO 和 SBDD 结合使用，作为一种有效的药物设计机制。
