Department of Biomedical Engineering and the Translational Tissue Engineering Center , The Johns Hopkins University , Baltimore , Maryland 21231 , United States.
Mol Pharm. 2018 Mar 5;15(3):705-720. doi: 10.1021/acs.molpharmaceut.7b00525. Epub 2017 Sep 13.
In this study, we catalog structure activity relationships (SAR) of several short chain fatty acid (SCFA)-modified hexosamine analogues used in metabolic glycoengineering (MGE) by comparing in silico and experimental measurements of physiochemical properties important in drug design. We then describe the impact of these compounds on selected biological parameters that influence the pharmacological properties and safety of drug candidates by monitoring P-glycoprotein (Pgp) efflux, inhibition of cytochrome P450 3A4 (CYP3A4), hERG channel inhibition, and cardiomyocyte cytotoxicity. These parameters are influenced by length of the SCFAs (e.g., acetate vs n-butyrate), which are added to MGE analogues to increase the efficiency of cellular uptake, the regioisomeric arrangement of the SCFAs on the core sugar, the structure of the core sugar itself, and by the type of N-acyl modification (e.g., N-acetyl vs N-azido). By cataloging the influence of these SAR on pharmacological properties of MGE analogues, this study outlines design considerations for tuning the pharmacological, physiochemical, and the toxicological parameters of this emerging class of small molecule drug candidates.
在这项研究中，我们通过比较代谢糖工程（MGE）中使用的几种短链脂肪酸（SCFA）修饰的己糖胺类似物的计算和实验测量，对其结构活性关系（SAR）进行了编目，这些测量对药物设计中的重要理化性质具有重要意义。然后，我们描述了这些化合物对所选生物学参数的影响，这些参数会影响候选药物的药理学性质和安全性，监测方法包括 P-糖蛋白（Pgp）外排、细胞色素 P450 3A4（CYP3A4）抑制、hERG 通道抑制和心肌细胞细胞毒性。这些参数受到 SCFA（例如乙酸盐与正丁酸）长度的影响，这些 SCFA 添加到 MGE 类似物中可提高细胞摄取效率，SCFA 在核心糖上的区域异构体排列、核心糖本身的结构以及 N-酰基修饰的类型（例如 N-乙酰基与 N-叠氮基）。通过编目这些 SAR 对 MGE 类似物的药理学性质的影响，本研究为调整此类新兴小分子药物候选物的药理学、理化和毒理学参数的设计提供了思路。
