Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

doi:10.1088/1674-1056/acd687

中国物理B ›› 2023, Vol. 32 ›› Issue (8): 88702-088702.doi: 10.1088/1674-1056/acd687

Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

Xin-Guan Tan(谭新官)¹, Xue-Feng Liu(刘雪峰)^1,†, Ming-Hui Pang(庞铭慧)¹, Yu-Qing Wang(王雨晴)¹, and Yun-Jie Zhao(赵蕴杰)^2,‡

1. College of Mathematics and Physics, Chengdu University of Technology, Chengdu 610059, China;
2. Institute of Biophysics and Department of Physics, Central China Normal University, Wuhan 430079, China

收稿日期:2023-02-27 修回日期:2023-04-17 接受日期:2023-05-18 发布日期:2023-07-14
通讯作者: Xue-Feng Liu, Yun-Jie Zhao E-mail:liuxuefeng17@cdut.edu.cn;yjzhaowh@mail.ccnu.edu.cn
基金资助:
Project supported by the National Natural Science Foundation of China (Grant Nos.11904036 and 12175081) and Fundamental Research Funds for the Central Universities (Grant No.CCNU22QNOO4).

Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

Xin-Guan Tan(谭新官)¹, Xue-Feng Liu(刘雪峰)^1,†, Ming-Hui Pang(庞铭慧)¹, Yu-Qing Wang(王雨晴)¹, and Yun-Jie Zhao(赵蕴杰)^2,‡

1. College of Mathematics and Physics, Chengdu University of Technology, Chengdu 610059, China;
2. Institute of Biophysics and Department of Physics, Central China Normal University, Wuhan 430079, China

Received:2023-02-27 Revised:2023-04-17 Accepted:2023-05-18 Published:2023-07-14
Contact: Xue-Feng Liu, Yun-Jie Zhao E-mail:liuxuefeng17@cdut.edu.cn;yjzhaowh@mail.ccnu.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China (Grant Nos.11904036 and 12175081) and Fundamental Research Funds for the Central Universities (Grant No.CCNU22QNOO4).

1. 2023-088702-SI.pdf(1207KB)

摘要/Abstract

摘要： The human serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft, which is an essential process that plays an important role in depression. In addition to natural substrate serotonin, SERT is also the target of the abused drug cocaine and, clinically used antidepressants, escitalopram, and paroxetine. To date, few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT. In this article, the conserved property of the orthosteric and allosteric sites (S1 and S2) of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics (MD) simulations. The residues Tyr95 and Ser438 located within the S1 site, and Arg104 located within the S2 site in SERT illustrate conserved interactions (hydrogen bonds and hydrophobic interactions), as responses to selective serotonin reuptake inhibitors. Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further, electrostatic interactions highlighted escitalopram as a potent antidepressant. We found that cocaine, escitalopram, and paroxetine, whether the S1 site or the S2 site, were more competitive. According to this potential of mean force (PMF) simulations, the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were ～ 18 Å for serotonin and ～ 22 Å for the above-mentioned three drugs. Furthermore, the distance between the natural substrate serotonin and cocaine (or escitalopram) at the allosteric site was ～ 3 Å. Thus, it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate. Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT, this study observed a broad pathway in which serotonin, cocaine, escitalopram (at the S1 site), and paroxetine all were pulled out to an opening between MT1b and MT6a, which may be helpful to understand the dissociation mechanism of antidepressants.

关键词: human serotonin transporter (SERT), comprehensive molecular dynamics (MD) simulation, drug design, molecular mechanics/generalized Born surface area (MM/GBSA) method

Abstract: The human serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft, which is an essential process that plays an important role in depression. In addition to natural substrate serotonin, SERT is also the target of the abused drug cocaine and, clinically used antidepressants, escitalopram, and paroxetine. To date, few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT. In this article, the conserved property of the orthosteric and allosteric sites (S1 and S2) of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics (MD) simulations. The residues Tyr95 and Ser438 located within the S1 site, and Arg104 located within the S2 site in SERT illustrate conserved interactions (hydrogen bonds and hydrophobic interactions), as responses to selective serotonin reuptake inhibitors. Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further, electrostatic interactions highlighted escitalopram as a potent antidepressant. We found that cocaine, escitalopram, and paroxetine, whether the S1 site or the S2 site, were more competitive. According to this potential of mean force (PMF) simulations, the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were ～ 18 Å for serotonin and ～ 22 Å for the above-mentioned three drugs. Furthermore, the distance between the natural substrate serotonin and cocaine (or escitalopram) at the allosteric site was ～ 3 Å. Thus, it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate. Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT, this study observed a broad pathway in which serotonin, cocaine, escitalopram (at the S1 site), and paroxetine all were pulled out to an opening between MT1b and MT6a, which may be helpful to understand the dissociation mechanism of antidepressants.

Key words: human serotonin transporter (SERT), comprehensive molecular dynamics (MD) simulation, drug design, molecular mechanics/generalized Born surface area (MM/GBSA) method

中图分类号: (Membrane proteins)

87.14.ep

87.15.A- (Theory, modeling, and computer simulation) 87.15.Cc (Folding: thermodynamics, statistical mechanics, models, and pathways)

Xin-Guan Tan(谭新官), Xue-Feng Liu(刘雪峰), Ming-Hui Pang(庞铭慧), Yu-Qing Wang(王雨晴), and Yun-Jie Zhao(赵蕴杰). Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants[J]. 中国物理B, 2023, 32(8): 88702-088702.

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Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

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