Goetz Gilles H, Shalaeva Marina, Caron Giulia, Ermondi Giuseppe, Philippe Laurence
Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer Inc. , Groton, Connecticut 06340, United States.
Molecular Biotechnology and Health Sciences Department, University of Torino , via Quarello 15, 10135 Torino, Italy.
Mol Pharm. 2017 Feb 6;14(2):386-393. doi: 10.1021/acs.molpharmaceut.6b00724. Epub 2017 Jan 17.
EPSA is an experimental descriptor of molecular polarity obtained from chromatographic retention in supercritical fluid chromatography (SFC) systems, previously shown by Goetz et al. to correlate with passive permeability of cyclic peptides. The present study focuses on EPSA in relation to passive permeability of small molecules. We applied block relevance (BR) analysis to interpret the relative significance of mechanistic forces prevailing in EPSA. The BR analysis is a computational tool that allows the interpretation of the balance of intermolecular interactions governing systems such as the aforementioned chromatographic retention in EPSA. EPSA and passive permeability determined by Ralph Russ canine kidney cells (RRCK) or low efflux Madin Darby canine kidney cells (MDCK-LE) and human epithelial colorectal adenocarcinoma cells (Caco-2), studied on a data set of commercial drugs, indicated that EPSA is relevant in describing permeability of hydrophilic drugs (CLogP < 1). We then verified, on a data set of 1699 Rule of 5 compliant Pfizer compounds, that when CLogP < 1, a value of EPSA < 100 significantly increases the likelihood of high permeability.
EPSA是一种通过超临界流体色谱（SFC）系统中的色谱保留获得的分子极性实验描述符，Goetz等人先前已证明其与环肽的被动通透性相关。本研究聚焦于与小分子被动通透性相关的EPSA。我们应用块相关性（BR）分析来解释EPSA中占主导地位的机械力的相对重要性。BR分析是一种计算工具，可用于解释控制诸如上述EPSA中色谱保留等系统的分子间相互作用的平衡。在一组商业药物数据集上进行研究，通过拉尔夫·拉斯犬肾细胞（RRCK）或低外排马德堡达尔比犬肾细胞（MDCK-LE）以及人上皮结肠腺癌细胞（Caco-2）测定的EPSA和被动通透性表明，EPSA在描述亲水性药物（CLogP < 1）的通透性方面具有相关性。然后，我们在一组1699种符合五规则的辉瑞化合物数据集上验证，当CLogP < 1时，EPSA < 100的值会显著增加高通透性的可能性。
