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

Cheng Peng; Yoseph Atilaw; Jinan Wang; Zhijian Xu; Vasanthanathan Poongavanam; Jiye Shi; Jan Kihlberg; Weiliang Zhu; Máté Erdélyi

doi:10.1021/acsomega.9b03797

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

ACS Omega. 2019 Dec 16;4(26):22245-22250. doi: 10.1021/acsomega.9b03797. eCollection 2019 Dec 24.

Authors

Cheng Peng^{1

2}, Yoseph Atilaw³, Jinan Wang¹, Zhijian Xu^{1

2}, Vasanthanathan Poongavanam³, Jiye Shi¹, Jan Kihlberg³, Weiliang Zhu^{1

2}, Máté Erdélyi³

Affiliations

¹ Drug Discovery and Design Center; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
² University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
³ Department of Chemistry-BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.

Abstract

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.