| Autor: |
Paulikat M; Computational Biomedicine, Institute of Advanced Simulations IAS-5/Institute for Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428 Jülich, Germany., Piccini G; Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany., Ippoliti E; Computational Biomedicine, Institute of Advanced Simulations IAS-5/Institute for Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428 Jülich, Germany., Rossetti G; Computational Biomedicine, Institute of Advanced Simulations IAS-5/Institute for Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428 Jülich, Germany.; Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich GmbH, 52428 Jülich, Germany.; Department of Neurology, RWTH Aachen University, Aachen 52062, Germany., Arnesano F; Department of Chemistry, University of Bari 'Aldo Moro', Bari 70125, Italy., Carloni P; Computational Biomedicine, Institute of Advanced Simulations IAS-5/Institute for Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428 Jülich, Germany.; Department of Physics, RWTH Aachen University, Aachen 52062, Germany. |
| Abstrakt: |
We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the antimalaria FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for the drug's action. Free energy values obtained by well-tempered metadynamics simulations suggest that the neutral form is the only permeating protomer, consistent with experimental data. H-bond interactions of the drug with water molecules and membrane headgroups play a crucial role for permeation. The presence of the transmembrane potential, investigated here for the first time in a drug permeation study, does not qualitatively affect these conclusions. |
