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Published October 29, 2019 | Version 1
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The Conformation of the Macrocyclic Drug Lorlatinib in Polar and Nonpolar Environments: a MD Simulation and NMR Study

Authors/Creators

  • 1. Peng
  • 2. Yoseph
  • 3. Jinan
  • 4. Zhijian
  • 5. Vasanthanathan
  • 6. Shi
  • 7. Jan
  • 8. Weiliang
  • 9. Mate

Contributors

Contact person:

Project leader:

  • 1. CAS Key Laboratory of Receptor Research
  • 2. Department of Chemistry - BMC, Uppsala University, SE-751 23 Uppsala, Sweden
  • 3. UCB Biohparma

Description

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 adapts 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 lorlatinibs ability to cross cell membranes.

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