极表面积
化学
药物发现
极性(国际关系)
计算生物学
吸收(声学)
组合化学
药品
生化工程
纳米技术
药理学
生物化学
工程类
有机化学
分子
材料科学
医学
细胞
生物
复合材料
作者
Edward Price,Manuel Weinheimer,Alexey Rivkin,Gary J. Jenkins,Marjoleen Nijsen,Philip B. Cox,David A. DeGoey
标识
DOI:10.1021/acs.jmedchem.3c02332
摘要
Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize absorption for rule of five (Ro5) compounds; beyond rule of five (bRo5) drugs necessitate advanced tools like the experimental measure of exposed polarity (EPSA) and the AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS and EPSA against ∼1000 compounds with human absorption data and ∼10,000 AbbVie tool compounds (∼1000 proteolysis targeting chimeras or PROTACs, ∼7000 Ro5s, and ∼2000 bRo5s) revealed new patterns of physicochemical trends. We introduced a high-throughput "polarity reduction" descriptor: ETR, the EPSA-to-topological polar surface area (TPSA) ratio, highlights unique bRo5 and PROTAC subsets for specialized drug design strategies for effective absorption. Our methods and guidelines refine drug design by providing innovative in vitro approaches, enhancing physicochemical property optimization, and enabling accurate predictions of intestinal absorption in the complex bRo5 domain.
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