Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants
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...
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Veröffentlicht in: | Chinese physics B 2023-07, Vol.32 (8), p.88702-591 |
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description | 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. |
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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.</description><identifier>ISSN: 1674-1056</identifier><identifier>DOI: 10.1088/1674-1056/acd687</identifier><language>eng</language><publisher>Chinese Physical Society and IOP Publishing Ltd</publisher><subject>comprehensive molecular dynamics (MD) simulation ; drug design ; human serotonin transporter (SERT) ; molecular mechanics/generalized Born surface area (MM/GBSA) method</subject><ispartof>Chinese physics B, 2023-07, Vol.32 (8), p.88702-591</ispartof><rights>2023 Chinese Physical Society and IOP Publishing Ltd</rights><rights>Copyright © Wanfang Data Co. Ltd. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c265t-57785bf34d9a617e0fe316f3ee5bc80f01a8785047005c28e891f8badea89a423</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.wanfangdata.com.cn/images/PeriodicalImages/zgwl-e/zgwl-e.jpg</thumbnail><linktopdf>$$Uhttps://iopscience.iop.org/article/10.1088/1674-1056/acd687/pdf$$EPDF$$P50$$Giop$$H</linktopdf><link.rule.ids>314,776,780,27901,27902,53821</link.rule.ids></links><search><creatorcontrib>Tan, Xin-Guan</creatorcontrib><creatorcontrib>Liu, Xue-Feng</creatorcontrib><creatorcontrib>Pang, Ming-Hui</creatorcontrib><creatorcontrib>Wang, Yu-Qing</creatorcontrib><creatorcontrib>Zhao, Yun-Jie</creatorcontrib><title>Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants</title><title>Chinese physics B</title><addtitle>Chin. Phys. B</addtitle><description>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.</description><subject>comprehensive molecular dynamics (MD) simulation</subject><subject>drug design</subject><subject>human serotonin transporter (SERT)</subject><subject>molecular mechanics/generalized Born surface area (MM/GBSA) method</subject><issn>1674-1056</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp1kDtPwzAUhT2ARCnsjN5YCL3O0x1RVR5SJSQos-X4EVzFdmQ3lPLrSRQEE9M9OjrnXOlD6IrALQFKF6Ss8oRAUS64kCWtTtDs1zpD5zHuAEoCaTZDx_Vn1_pgXIN7VxsnR2WVeOfORIu9xjL0TcQ6eItf1y9b_GE4tr5Vom95wPLouDUi4mjsYOyNd5g7ic0-YmO71ojJM6O9N1J1QcU4yHiBTjVvo7r8uXP0dr_erh6TzfPD0-puk4i0LPZJUVW0qHWWyyUvSaVAq4yUOlOqqAUFDYTTIQF5BVCIlCq6JJrWXCpOlzxPszm6nnYP3GnuGrbzfXDDR_bVHFqm0oEDUKjGJExJEXyMQWnWBWN5ODICbATLRopspMgmsEPlZqoY3_0N_xv_BjwIfio</recordid><startdate>20230701</startdate><enddate>20230701</enddate><creator>Tan, Xin-Guan</creator><creator>Liu, Xue-Feng</creator><creator>Pang, Ming-Hui</creator><creator>Wang, Yu-Qing</creator><creator>Zhao, Yun-Jie</creator><general>Chinese Physical Society and IOP Publishing Ltd</general><general>College of Mathematics and Physics,Chengdu University of Technology,Chengdu 610059,China%Institute of Biophysics and Department of Physics,Central China Normal University,Wuhan 430079,China</general><scope>AAYXX</scope><scope>CITATION</scope><scope>2B.</scope><scope>4A8</scope><scope>92I</scope><scope>93N</scope><scope>PSX</scope><scope>TCJ</scope></search><sort><creationdate>20230701</creationdate><title>Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants</title><author>Tan, Xin-Guan ; Liu, Xue-Feng ; Pang, Ming-Hui ; Wang, Yu-Qing ; Zhao, Yun-Jie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c265t-57785bf34d9a617e0fe316f3ee5bc80f01a8785047005c28e891f8badea89a423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>comprehensive molecular dynamics (MD) simulation</topic><topic>drug design</topic><topic>human serotonin transporter (SERT)</topic><topic>molecular mechanics/generalized Born surface area (MM/GBSA) method</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tan, Xin-Guan</creatorcontrib><creatorcontrib>Liu, Xue-Feng</creatorcontrib><creatorcontrib>Pang, Ming-Hui</creatorcontrib><creatorcontrib>Wang, Yu-Qing</creatorcontrib><creatorcontrib>Zhao, Yun-Jie</creatorcontrib><collection>CrossRef</collection><collection>Wanfang Data Journals - Hong Kong</collection><collection>WANFANG Data Centre</collection><collection>Wanfang Data Journals</collection><collection>万方数据期刊 - 香港版</collection><collection>China Online Journals (COJ)</collection><collection>China Online Journals (COJ)</collection><jtitle>Chinese physics B</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tan, Xin-Guan</au><au>Liu, Xue-Feng</au><au>Pang, Ming-Hui</au><au>Wang, Yu-Qing</au><au>Zhao, Yun-Jie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants</atitle><jtitle>Chinese physics B</jtitle><addtitle>Chin. Phys. B</addtitle><date>2023-07-01</date><risdate>2023</risdate><volume>32</volume><issue>8</issue><spage>88702</spage><epage>591</epage><pages>88702-591</pages><issn>1674-1056</issn><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.</abstract><pub>Chinese Physical Society and IOP Publishing Ltd</pub><doi>10.1088/1674-1056/acd687</doi><tpages>10</tpages></addata></record> |
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title | Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants |
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