Tan, X.-G.; Liu, X.-F.; Pang, M.-H.; Wang, Y.-Q.; Zhao, Y.-J. Exploring the Unbinding Mechanism of Drugs from SERT via Molecular Dynamics Simulation and Its Implication in Antidepressants*. Chinese Physics B 2023, doi:10.1088/1674-1056/acd687.
Tan, X.-G.; Liu, X.-F.; Pang, M.-H.; Wang, Y.-Q.; Zhao, Y.-J. Exploring the Unbinding Mechanism of Drugs from SERT via Molecular Dynamics Simulation and Its Implication in Antidepressants*. Chinese Physics B 2023, doi:10.1088/1674-1056/acd687.
Tan, X.-G.; Liu, X.-F.; Pang, M.-H.; Wang, Y.-Q.; Zhao, Y.-J. Exploring the Unbinding Mechanism of Drugs from SERT via Molecular Dynamics Simulation and Its Implication in Antidepressants*. Chinese Physics B 2023, doi:10.1088/1674-1056/acd687.
Tan, X.-G.; Liu, X.-F.; Pang, M.-H.; Wang, Y.-Q.; Zhao, Y.-J. Exploring the Unbinding Mechanism of Drugs from SERT via Molecular Dynamics Simulation and Its Implication in Antidepressants*. Chinese Physics B 2023, doi:10.1088/1674-1056/acd687.
Abstract
The human serotonin transporter (hSERT) terminates neurotransmission by removing serotonin from the synaptic cleft, which is an essential process plays an important role in depression. In addition to substrate serotonin, hSERT is also the target of drugs of abuse like cocaine and clinically used antidepressants such as escitalopram and paroxetine. To date, few studies attempt to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of hSERT. The high-resolution X-ray structure of hSERT resolved recently enables us to theoretically study the unbinding of the above four ligands against the S1 or S2 site of hSERT, by means of molecular docking, molecular dynamics (MD) and potential of mean force (PMF) simulations. We proved that for either the S1 or S2 site, the other three ligands (cocaine, escitalopram and paroxetine) are much more favorable than the original substrate serotonin, whether in kinetics along the unbinding pathways or in thermodynamics at the equilibrium states. Furthermore, the S1 site is much more favorable than the S2 site, for each ligand. Interestingly, inspection revealed that there are ~ 3Å lengths between the allosteric site of serotonin and cocaine, and an unseen un-binding pathway for escitalopram at the S1 site except for verification of the broadest trail.
Keywords
hSERT; comprehensive molecular dynamics (MD) simulation; drug design; MM/GBSA
Subject
Biology and Life Sciences, Biophysics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
