Issue 4, 2016

Identification of the inhibitory mechanism of FDA approved selective serotonin reuptake inhibitors: an insight from molecular dynamics simulation study

Abstract

Antidepressants selectively inhibiting serotonin reuptake (SSRIs) represent a highly effective drug class, and novel therapeutic strategies were proposed to improve SSRIs' drug efficacy. The knowledge of the inhibitory mechanism of FDA approved SSRIs could provide great insights and act as important starting points to discover privileged drug scaffolds with improved efficacy. However, the structure of human serotonin transporter (hSERT) is yet to be determined and the inhibitory mechanism underlying SSRIs still needs to be further explored. In this study, the inhibitory mechanism of 4 approved SSRIs treating major depression (fluoxetine, sertraline, paroxetine and escitalopram) was identified by integrating multiple computational methods. Firstly, a recently published template with high sequence identity was adopted for the first time to generate hSERT's homology model. Then, docking poses of 4 SSRIs were used as the initial conformation for molecular dynamics (MD) simulation followed by MM/GBSA binding free energy calculation and per-residue free energy decomposition. Finally, the binding mode shared by the 4 studied SSRIs was identified by hierarchically clustering per-residue free energies. The identified binding mode was composed of collective interactions between 3 chemical groups in SSRIs and 11 hot spot residues in hSERT. 6 out of these 11 were validated by previous mutagenesis studies or pharmacophore models, and the remaining 5 (Ala169, Ala173, Thr439, Gly442 and Leu443) found in this work were not yet been identified as common determinants of all the 4 studied SSRIs in binding hSERT. Moreover, changes in SSRIs' binding induced by mutation on hot spot residues were further explored, and 3 mechanisms underlining their drug sensitivity were summarized. In summary, the identified binding mode provided important insights into the inhibitory mechanism of approved SSRIs treating major depression, which could be further utilized as a framework for assessing and discovering novel lead scaffolds.

Graphical abstract: Identification of the inhibitory mechanism of FDA approved selective serotonin reuptake inhibitors: an insight from molecular dynamics simulation study

Supplementary files

Article information

Article type
Paper
Submitted
26 Sep 2015
Accepted
20 Dec 2015
First published
21 Dec 2015

Phys. Chem. Chem. Phys., 2016,18, 3260-3271

Author version available

Identification of the inhibitory mechanism of FDA approved selective serotonin reuptake inhibitors: an insight from molecular dynamics simulation study

W. Xue, P. Wang, B. Li, Y. Li, X. Xu, F. Yang, X. Yao, Y. Z. Chen, F. Xu and F. Zhu, Phys. Chem. Chem. Phys., 2016, 18, 3260 DOI: 10.1039/C5CP05771J

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements