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

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journal contribution
posted on 2019-12-16, 09:29 authored by Cheng Peng, Yoseph Atilaw, Jinan Wang, Zhijian Xu, Vasanthanathan Poongavanam, Jiye Shi, Jan Kihlberg, Weiliang Zhu, Máté Erdélyi
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.

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