Conformation of the Macrocyclic Drug Lorlatinib in Polar and Nonpolar Environments: A MD Simulation and NMR Study

The replica exchange molecular dynamics (REMD) simulation is demonstrated to readily predict the conformations of the macrocyclic drug lorlatinib, as validated by solution NMR studies. In aqueous solution, lorlatinib adopts a conformer identical to its target bound structure. This conformer is stabilized by an extensive hydrogen bond network to the solvents. In chloroform, lorlatinib populates two conformers with the second one being less polar, which may contribute to lorlatinib’s ability to cross cell membranes.副本交换分子动力学（Replica Exchange Molecular Dynamics, REMD）模拟已被证实可高效预测大环类药物洛拉替尼（lorlatinib）的构象，该结论经溶液态核磁共振（NMR）研究验证。在水溶液中，洛拉替尼所呈现的构象与其靶点结合结构完全一致，该构象通过与溶剂间形成的广泛氢键网络得以稳定。在氯仿溶剂中，洛拉替尼存在两种构象，其中第二种极性更低，这一特性或有助于洛拉替尼实现跨细胞膜的能力。