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5-HTR2B and SLC6A3 as potential molecular targets of sertraline in the treatment of major depressive disorder: the use of bioinformatics and its practical implication

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Abstract

Major depressive disorder (MDD) is known to be a highly limiting and disabling disorder worldwide. The main management for this disorder is based on pharmacological therapy with antidepressants, especially in moderate to severe presentations. Among these, selective serotonin reuptake inhibitors (SSRIs) are, at the moment, the most widely prescribed class. Individualized pharmacological therapy presents itself as a powerful tool to reduce the course of the disorder, especially if one takes into account the potential molecular targets and the relationship of these targets in MDD pharmacotherapy. To explore this possibility, using bioinformatics approaches, we combined two reverse molecular screening approaches, followed by traditional docking simulations to identify potential molecular targets specifically for sertraline. According to our results, sertraline presented 17 potential targets, 4 in common within both inverse screening approaches, and were analyzed in our study: 5-HTR2B (5-hydroxytryptamine receptor 2B subtype), SLC6A2 (norepinephrine transporter), SLC6A3 (dopamine transporter) and SLC6A4 (serotonin transporter). Traditional docking simulations revealed higher interaction energies of 5-HTR2B and SLC6A3 with the sertraline molecule. In addition, both proteins are directly or indirectly related to the modulation of serotonin and dopamine, as well as the rate of response to SSRIs. Therefore, we suggest that the interaction of sertraline with the 5-HTR2B and SLC6A3 proteins points to a multimodal mechanism of pharmacological action, especially for the treatment of MDD.

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References

  • Aggarwal S, Mortensen OV (2018) Overview of monoamine transporters. Curr Protoc Pharmacol 79:12.16.1-12.16.17

    Google Scholar 

  • APA, 2013. Diagnostic and statistical manual of mental disorders DSM 5, 5a. ed, 5a. Ed. Rev. Porto Alegre Artmed.

  • Bahi A, Dreyer JL (2019) Dopamine transporter (DAT) knockdown in the nucleus accumbens improves anxiety- and depression-related behaviors in adult mice. Behav Brain Res 359:104–115

    Article  Google Scholar 

  • Banas SM, Doly S, Boutourlinsky K, Diaz SL, Belmer A, Callebert J, Collet C, Launay JM, Maroteaux L (2011) Deconstructing antiobesity compound action: requirement of serotonin 5-HT 2B receptors for dexfenfluramine anorectic effects. Neuropsychopharmacology 36:423–433

    Article  Google Scholar 

  • Baudry A, Pietri M, Launay JM, Kellermann O, Schneider B (2019) Multifaceted regulations of the serotonin transporter: impact on antidepressant response. Front Neurosci 13:1–13

    Article  Google Scholar 

  • Belmer A, Quentin E, Diaz SL, Guiard BP, Fernandez SP, Doly S, Banas SM, Pitychoutis PM, Moutkine I, Muzerelle A, Tchenio A, Roumier A, Mameli M, Maroteaux L (2018) Positive regulation of raphe serotonin neurons by serotonin 2B receptors. Neuropsychopharmacology 43:1623–1632

    Article  Google Scholar 

  • Belujon P, Grace AA (2017) Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol 20:1036–1046

    Article  Google Scholar 

  • Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101

    Article  Google Scholar 

  • Chen D, Meng L, Pei F, Zheng Y, Leng J (2017) A review of DNA methylation in depression. J Clin Neurosci 43:39–46

    Article  Google Scholar 

  • Cheng MH, Bahar I (2019) Monoamine transporters: structure, intrinsic dynamics and allosteric regulation. Nat Struct Mol Biol 26:545–556

    Article  Google Scholar 

  • Cipriani A, Ruhe HG, Furukawa TA, Tajika A, Egger M, Hayasaka Y, Higgins JPT, Atkinson LZ, Shinohara K, Ioannidis JPA, Leucht S, Ogawa Y, Salanti G, Takeshima N, Imai H, Turner EH, Chaimani A, Geddes JR (2018) Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391:1357–1366

    Article  Google Scholar 

  • D’Souza S, Thompson JMD, Slykerman R, Marlow G, Wall C, Murphy R, Ferguson LR, Mitchell EA, Waldie KE (2016) Environmental and genetic determinants of childhood depression: the roles of DAT1 and the antenatal environment. J Affect Disord 197:151–158

    Article  Google Scholar 

  • Daina A, Michielin O, Zoete V (2019) Swisstargetprediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 47:W357–W364

    Article  Google Scholar 

  • Diaz SL, Maroteaux L (2011) Implication of 5-HT2B receptors in the serotonin syndrome. Neuropharmacology 61:495–502

    Article  Google Scholar 

  • Diaz SL, Doly S, Narboux-Nme N, Fernández S, Mazot P, Banas SM, Boutourlinsky K, Moutkine I, Belmer A, Roumier A, Maroteaux L (2012) 5-HT 2B receptors are required for serotonin-selective antidepressant actions. Mol Psychiatry 17:154–163

    Article  Google Scholar 

  • Diaz SL, Narboux-Nême N, Boutourlinsky K, Doly S, Maroteaux L (2016) Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants. Eur Neuropsychopharmacol 26:265–279

    Article  Google Scholar 

  • Dogan O, Yuksel N, Ergun MA, Yilmaz A, Ilhan MN, Karslioglu HE, Koc A, Menevse A (2008) Serotonin transporter gene polymorphisms and sertraline response in major depression patients. Genet Test 12:225–231

    Article  Google Scholar 

  • Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L (2008) Serotonin 5-HT2B receptors are required for 3,4- methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro. J Neurosci 28:2933–2940

    Article  Google Scholar 

  • Doly S, Bertran-Gonzalez J, Callebert J, Bruneau A, Banas SM, Belmer A, Boutourlinsky K, Hervé D, Launay JM, Maroteaux L (2009) Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice. PLoS ONE 4:1–10

    Article  Google Scholar 

  • Doly S, Quentin E, Eddine R, Tolu S, Fernandez SP, Bertran-Gonzalez J, Valjent E, Belmer A, Viñals X, Callebert J, Faure P, Meye FJ, Hervé D, Robledo P, Mameli M, Launay JM, Maldonado R, Maroteaux L (2017) Serotonin 2B receptors in mesoaccumbens dopamine pathway regulate cocaine responses. J Neurosci 37:10372–10388

    Article  Google Scholar 

  • Duman RS, Deyama S, Fogaça MV (2021) Role of BDNF in the pathophysiology and treatment of depression: activity-dependent effects distinguish rapid-acting antidepressants. Eur J Neurosci 53:126–139

    Article  Google Scholar 

  • Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB (2004) The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology 174:525–529

    Article  Google Scholar 

  • Fan H, Schneidman-Duhovny D, Irwin JJ, Dong G, Shoichet BK, Sali A (2011) Statistical potential for modeling and ranking of protein-ligand interactions. J Chem Inf Model 51:3078–3092

    Article  Google Scholar 

  • Fishback JA, Robson MJ, Xu YT, Matsumoto RR (2010) Sigma receptors: potential targets for a new class of antidepressant drug. Pharmacol Ther 127:271–282

    Article  Google Scholar 

  • Gartlehner G, Wagner G, Matyas N, Titscher V, Greimel J, Lux L, Gaynes BN, Viswanathan M, Patel S, Lohr KN (2017) Pharmacological and non- pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 7:1–13

    Article  Google Scholar 

  • Goldman D, Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T, Zhou Z, Wedenoja J, Maroteaux L, Diaz S, Belmer A, Colin AH, Dell’Osso L, Suvisaari J, Coccaro E, Rose RJ, Peltonen L, Virkkunen M (2010) A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 468:1061–1068

    Article  Google Scholar 

  • Grace AA (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 17:524–532

    Article  Google Scholar 

  • Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, Grant BF (2018) Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiat 75:336–346

    Article  Google Scholar 

  • Hertz L, Rothman DL, Li B, Peng L (2015) Chronic ssri stimulation of astrocytic 5- HT2B receptors change multiple gene expressions/editings and metabolism of glutamate, glucose and glycogen: a potential paradigm shift. Front Behav Neurosci 9:1–17

    Google Scholar 

  • Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

    Article  Google Scholar 

  • Hiemke C, Härtter S (2000) Pharmacokinetics of the selective serotonin reuptake inhibitors. Pharmacol Ther 85:11–20

    Article  Google Scholar 

  • Hieronymus F, Emilsson JF, Nilsson S, Eriksson E (2016) Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. Mol Psychiatry 21:523–530

    Article  Google Scholar 

  • Huang SY, Zou X (2010) Advances and challenges in protein-ligand docking. Int J Mol Sci 11:3016–3034

    Article  Google Scholar 

  • Jorgensen WL, Chandrasekhar J, Madura JD (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926

    Article  Google Scholar 

  • Kagami LP, das Neves GM, Timmers LFSM, Caceres RA, Eifler-Lima VL (2020) Geo-measures: A PyMOL plugin for protein structure ensembles analysis. Comput Biol Chem. 87:107322

    Article  Google Scholar 

  • Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, Hasnain M, Jollant F, Levitt AJ, MacQueen GM, McInerney SJ, McIntosh D, Milev RV, Müller DJ, Parikh SV, Pearson NL, Ravindran AV, Uher R (2016) Canadian Network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3 pharmacological treatments. Can J Psychiatry 61:540–560

    Article  Google Scholar 

  • Kirchheiner J, Nickchen K, Sasse J, Bauer M, Roots I, Brockmöller J (2007) A 40- basepair VNTR polymorphism in the dopamine transporter (DAT1) gene and the rapid response to antidepressant treatment. Pharmacogenomics J 7:48–55

    Article  Google Scholar 

  • Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, Koyama T (2010) Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. Eur J Pharmacol 647:90–96

    Article  Google Scholar 

  • Larsen MB, Sonders MS, Mortensen OV, Larson GA, Zahniser NR, Amara SG (2011) Dopamine transport by the serotonin transporter: a mechanistically distinct mode of substrate translocation. J Neurosci 31:6605–6615

    Article  Google Scholar 

  • Launay J, Schneider B, Loric S, Prada MD, Kellermann O (2006) Serotonin transport and serotonin transporter- mediated antidepressant recognition are controlled by 5- HT2B receptor signaling in serotonergic neuronal cells. FASEB J 20:1843–1854

    Article  Google Scholar 

  • Lee A, Lee K, Kim D (2016) Using reverse docking for target identification and its applications for drug discovery. Expert Opin Drug Discov 11:707–715

    Article  Google Scholar 

  • Li M, D’Arcy C, Li X, Zhang T, Joober R, Meng X (2019) What do DNA methylation studies tell us about depression? A systematic review. Transl Psychiatry 9:1–14

    Article  Google Scholar 

  • Malhi GS, Mann JJ (2018) Depression. Lancet 392:2299–2312

    Article  Google Scholar 

  • McCorvy JD, Wacker D, Wang S, Agegnehu B, Liu J, Lansu K, Tribo AR, Olsen RHJ, Che T, Jin J, Roth BL (2018) Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol 25:787–796

    Article  Google Scholar 

  • Moal IH, Torchala M, Bates PA, Fernández-Recio J (2013) The scoring of poses in protein-protein docking: current capabilities and future directions. BMC Bioinformatics 14:286

    Article  Google Scholar 

  • Moriguchi S, Yamada M, Takano H, Nagashima T, Takahata K, Yokokawa K, Ito T, Ishii T, Kimura Y, Zhang MR, Mimura M, Suhara T (2017) Norepinephrine transporter in major depressive disorder: a PET study. Am J Psychiatry 174:36–41

    Article  Google Scholar 

  • Mulvihill KG (2019) Presynaptic regulation of dopamine release: role of the DAT and VMAT2 transporters. Neurochem Int 122:94–105

    Article  Google Scholar 

  • Mushtaq D, Ali A, Margoob MA, Murtaza I, Andrade C (2012) Association between serotonin transporter gene promoter-region polymorphism and 4- and 12-week treatment response to sertraline in posttraumatic stress disorder. J Affect Disord 136:955–962

    Article  Google Scholar 

  • Naga Madhavilatha, K., Rama Mohan Babu, G., 2019. Systematic approach for enrichment of docking outcome using consensus scoring functions. J. Phys. Conf. Ser. 1228.

  • Nikolova YS, Koenen KC, Galea S, Wang CM, Seney ML, Sibille E, Williamson DE, Hariri AR (2014) Beyond genotype: serotonin transporter epigenetic modification predicts human brain function. Nat Neurosci 17:1153–1155

    Article  Google Scholar 

  • Pan Z, Park C, Brietzke E, Zuckerman H, Rong C, Mansur RB, Fus D, Subramaniapillai M, Lee Y, McIntyre RS (2019) Cognitive impairment in major depressive disorder. CNS Spectr 24:22–29

    Article  Google Scholar 

  • Parikh SV, Quilty LC, Ravitz P, Rosenbluth M, Pavlova B, Grigoriadis S, Velyvis V, Kennedy SH, Lam RW, MacQueen GM, Milev RV, Ravindran AV, Uher R (2016) Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 2 psychological treatments. Can J Psychiatry 61:524–539

    Article  Google Scholar 

  • Parker G, Blanch B, Paterson A, Hadzi-Pavlovic D, Sheppard E, Manicavasagar V, Synnott H, Graham RK, Friend P, Gilfillan D, Perich T (2013) The superiority of antidepressant medication to cognitive behavior therapy in melancholic depressed patients: a 12-week single-blind randomized study. Acta Psychiatr Scand 128(4):271–281

    Google Scholar 

  • Peciña M, Sikora M, Avery ET, Heffernan J, Peciña S, Mickey BJ, Zubieta J-K (2017) Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: implications for anhedonia, anxiety and treatment response. Eur Neuropsychopharmacol 27:977–986

    Article  Google Scholar 

  • Poweleit EA, Aldrich SL, Martin LJ, Hahn D, Strawn JR, Ramsey LB (2019) Pharmacogenetics of sertraline tolerability and response in pediatric anxiety and depressive disorders. J Child Adolesc Psychopharmacol 29:348–361

    Article  Google Scholar 

  • Rafeyan R, Papakostas GI, Jackson WC, Trivedi MH (2020) Inadequate response to treatment in major depressive disorder: augmentation and adjunctive strategies. J Clin Psychiatry 81:OT19037BR3

    Article  Google Scholar 

  • Rehm J, Shield KD (2019) Global burden of disease and the impact of mental and addictive disorders. Curr Psychiatry Rep 21:1–7

    Article  Google Scholar 

  • Saikia S, Bordoloi M (2019) Molecular docking: challenges, advances and its use in drug discovery perspective. Curr Drug Targets 20:501–521

    Article  Google Scholar 

  • Salatino-Oliveira A, Rohde LA, Hutz MH (2018) The dopamine transporter role in psychiatric phenotypes. Am J Med Genet B Neuropsychiatr Genet 177:211–231

    Article  Google Scholar 

  • Šali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815

    Article  Google Scholar 

  • Sanchez C, Reines EH, Montgomery SA (2014) A comparative review of escitalopram, paroxetine, and sertraline: are they all alike? Int Clin Psychopharmacol 29:185–196

    Article  Google Scholar 

  • Sangkuhl K, Klein TE, Altman RB (2009) Selective serotonin reuptake inhibitors pathway. Pharmacogenet Genomics 19:907–909

    Article  Google Scholar 

  • Shen M, Sali A (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15:2507–2524

    Article  Google Scholar 

  • Shumay E, Fowler JS, Volkow ND (2010) Genomic features of the human dopamine transporter gene and its potential epigenetic states: Implications for phenotypic diversity. PLoS ONE 5:1–17

    Article  Google Scholar 

  • Sousa da Silva AW, Vranken WF (2012) ACPYPE - antechamber python parser interface. BMC Res Notes 5:367

    Article  Google Scholar 

  • Staeker J, Leucht S, Laika B, Steimer W (2014) Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. Genet Test Mol Biomarkers 18:20–31

    Article  Google Scholar 

  • Stierand K, Maaß PC, Rarey M (2006) Molecular complexes at a glance: Automated generation of two-dimensional complex diagrams. Bioinformatics 22:1710–1716

    Article  Google Scholar 

  • Studer G, Rempfer C, Waterhouse AM, Gumienny R, Haas J, Schwede T (2020) QMEANDisCo—distance constraints applied on model quality estimation. Bioinformatics 36:1765–1771

    Article  Google Scholar 

  • van de Giessen EM, De Win MML, Tanck MWT, Van Den Brink W, Baas F, Booij J (2009) Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med 50:45–52

    Article  Google Scholar 

  • van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718

    Article  Google Scholar 

  • van Eeden WA, van Hemert AM, Carlier IVE, Penninx BW, Giltay EJ (2019) Severity, course trajectory, and within-person variability of individual symptoms in patients with major depressive disorder. Acta Psychiatr Scand 139:194–205

    Article  Google Scholar 

  • Vangone A, Bonvin AMJJ (2017) PRODIGY: a contact-based predictor of binding affinity in protein-protein complexes. Bio-Protoc 7:e2124

    Article  Google Scholar 

  • Wang KH, Penmatsa A, Gouaux E (2015) Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature 521:322–327

    Article  Google Scholar 

  • Wang Z, Liang L, Yin Z, Lin J (2016) Improving chemical similarity ensemble approach in target prediction. J Cheminform 8:1–10

    Article  Google Scholar 

  • Won E, Choi S, Kang J, Kim A, Han KM, Chang HS, Tae WS, Son KR, Joe SH, Lee MS, Ham BJ (2016) Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder. Transl Psychiatry 6:e866–e869

    Article  Google Scholar 

  • World Health Organization, 2020. Depression [WWW Document]. January 30, 2020. URL https://www.who.int/news-room/fact-sheets/detail/depression (accessed 7.5.20).

  • Xu X, Huang M, Zou X (2018) Docking-based inverse virtual screening: methods, applications, and challenges. Biophys Rep 4:1–16

    Article  Google Scholar 

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Acknowledgements

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant number: 407537/2018); the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, financial code 001).

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  1. Biotechnology Graduate Program, Universidade do Vale do Taquari - Univates, Lajeado, Brazil

    Ronaldo R. de Oliveira, Diana Kuhn, Daiane Heidrich, Rodrigo G. Ducati & Luís Fernando S. M. Timmers

  2. Medical Sciences Graduate Program, Universidade do Vale do Taquari - Univates, Lajeado, Brazil

    Daiane Heidrich, Flávio M. Shansis & Luís Fernando S. M. Timmers

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  1. Ronaldo R. de Oliveira
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de Oliveira, R.R., Kuhn, D., Heidrich, D. et al. 5-HTR2B and SLC6A3 as potential molecular targets of sertraline in the treatment of major depressive disorder: the use of bioinformatics and its practical implication. Netw Model Anal Health Inform Bioinforma 11, 34 (2022). https://doi.org/10.1007/s13721-022-00378-y

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