亲脂性
化学
氨基酸
分子动力学
组合化学
膜透性
膜
分子
立体化学
有机化学
计算化学
生物化学
作者
George J. Saunders,Andrei K. Yudin
标识
DOI:10.1002/anie.202206866
摘要
Abstract Passive membrane permeability is a fundamental challenge in the development of bioactive macrocycles. To achieve this objective, chemists have resorted to various strategies, the most common of which is deployment of N ‐methylated amino acids and/or D‐amino acids. Here we investigate the effect of heterocyclic grafts on the passive membrane permeability of macrocycles and report the structural consequences of iterative amino acid replacement by azole rings. Through stepwise substitution of amino acid residues for heterocycles, we show that lipophilicity and PAMPA permeability of a macrocycle can be vastly improved. Overall, changes in permeability do not scale linearly as more heterocycles are incorporated, underscoring the subtleties of conformation‐property relationships in this class of molecule. NMR analysis and molecular dynamics simulations provide insights into the structural consequences of the added heterocycles and these frameworks can now be applied as macrocyclic scaffolds for drug discovery.
科研通智能强力驱动
Strongly Powered by AbleSci AI