The binding mode of vilazodone in the human serotonin transporter elucidated by ligand docking and molecular dynamics simulations.

Vilazodone is a novel antidepressant used for the treatment of major depressive disorder (MDD) with a primary action mechanism of inhibiting the human serotonin reuptake transporter (hSERT) and acting as a 5-HT1A receptor partial agonist. The interaction between vilazodone and the 5-HT1A receptor has been reported, however, the binding mode of vilazodone in the hSERT remains elusive. In the current study, to elucidate the molecular mechanism of vilazodone binding in the hSERT, the drug and its five analogs were docked into the hSERT crystal structure as initial conformations and were sampled by 400 ns molecular dynamics (MD) simulations. Through the analysis of the profiles of protein-ligand binding free energies, interaction fingerprints, and conformational rearrangements, the binding mode of vilazodone in the hSERT was revealed. As a result, unlike the classical antidepressants located in the S1 site of the hSERT, vilazodone adopted a linear pose in the binding pocket. Its arylpiperazine fragment occupies the central site (S1) and interacts with Y95, D98, I172, Y176, F335, F341, S438, and T439, while the indole fragment extends to the allosteric site (S2) via interacting with the ionic switch (R104/E403) between the two sites. The new insights obtained are not only helpful in understanding the binding mode of vilazodone in the hSERT, but also provide valuable guidance to the discovery of novel antidepressant drugs.

[1]  G. Bartoszyk,et al.  EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. , 1997, European journal of pharmacology.

[2]  W. C. Still,et al.  Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO) , 1999 .

[3]  D. Weinberger,et al.  Serotonergic dysfunction, negative mood states, and response to alcohol. , 2001, Alcoholism, clinical and experimental research.

[4]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[5]  S. Anzali,et al.  Synthesis and Structure−Activity Relationship in a Class of Indolebutylpiperazines as Dual 5-HT1A Receptor Agonists and Serotonin Reuptake Inhibitors , 2004 .

[6]  T. Heinrich,et al.  Dual 5-HT1A agonists and 5-HT re-uptake inhibitors by combination of indole-butyl-amine and chromenonyl-piperazine structural elements in a single molecular entity. , 2004, Bioorganic & medicinal chemistry.

[7]  C. Langmead,et al.  Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone. , 2005, European journal of pharmacology.

[8]  D. Kupfer,et al.  Acute and Longer- Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report , 2006 .

[9]  Gilles Marcou,et al.  Optimizing Fragment and Scaffold Docking by Use of Molecular Interaction Fingerprints , 2007, J. Chem. Inf. Model..

[10]  T. Cheatham,et al.  Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations , 2008, The journal of physical chemistry. B.

[11]  Eric J. Nestler,et al.  The molecular neurobiology of depression , 2008, Nature.

[12]  D. E. Nichols,et al.  Serotonin receptors. , 2008, Chemical reviews.

[13]  L. Çelik,et al.  Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation. , 2008, Journal of the American Chemical Society.

[14]  Arif Khan.  Vilazodone, a novel dual-acting serotonergic antidepressant for managing major depression , 2009, Expert opinion on investigational drugs.

[15]  M. Briley,et al.  Review: Problems associated with long-term treatment with selective serotonin reuptake inhibitors , 2009, Journal of psychopharmacology.

[16]  M. Athanasiou,et al.  Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. , 2009, The Journal of clinical psychiatry.

[17]  Trina E. Chang,et al.  The future of psychopharmacology of depression. , 2010, The Journal of clinical psychiatry.

[18]  M. Athanasiou,et al.  A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. , 2011, The Journal of clinical psychiatry.

[19]  C. Hopkins.  ACS chemical neuroscience molecule spotlight on viibryd (Vilazodone). , 2011, ACS chemical neuroscience.

[20]  M. Millan,et al.  Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs , 2011, Neurotherapeutics.

[21]  C. Reed,et al.  A 1-Year, Open-Label Study Assessing the Safety and Tolerability of Vilazodone in Patients With Major Depressive Disorder , 2011, Journal of clinical psychopharmacology.

[22]  M. Liebowitz,et al.  The Safety and Tolerability Profile of Vilazodone, A Novel Antidepressant for the Treatment of Major Depressive Disorder. , 2011, Psychopharmacology bulletin.

[23]  Tingjun Hou,et al.  Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations , 2011, J. Chem. Inf. Model..

[24]  J. Frampton.  Vilazodone: in major depressive disorder. , 2011, CNS drugs.

[25]  G. Fricchione,et al.  Generalized anxiety disorder: diagnosis and treatment , 2012, BMJ : British Medical Journal.

[26]  Ellen Frank,et al.  Major depressive disorder: new clinical, neurobiological, and treatment perspectives , 2012, The Lancet.

[27]  Hyeon Joo,et al.  OPM database and PPM web server: resources for positioning of proteins in membranes , 2011, Nucleic Acids Res..

[28]  J. Madura,et al.  Monoamine Transporter Structure, Function, Dynamics, and Drug Discovery: A Computational Perspective , 2012, The AAPS Journal.

[29]  L. Citrome.  Vilazodone for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? , 2012, International journal of clinical practice.

[30]  Didier Rognan,et al.  Encoding Protein-Ligand Interaction Patterns in Fingerprints and Graphs , 2013, J. Chem. Inf. Model..

[31]  E. Gouaux,et al.  Structural basis for action by diverse antidepressants on biogenic amine transporters , 2013, Nature.

[32]  P. Celada,et al.  Serotonin 5-HT1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research , 2013, CNS Drugs.

[33]  S. Kortagere,et al.  Identification of an allosteric modulator of the serotonin transporter with novel mechanism of action , 2013, Neuropharmacology.

[34]  Sunhwan Jo,et al.  CHARMM‐GUI Membrane Builder toward realistic biological membrane simulations , 2014, J. Comput. Chem..

[35]  N. Pomara,et al.  Efficacy and safety of vilazodone in major depressive disorder: a randomized, double-blind, placebo-controlled trial. , 2014, The Journal of clinical psychiatry.

[36]  Benjamin D. Madej,et al.  Lipid14: The Amber Lipid Force Field , 2014, Journal of chemical theory and computation.

[37]  S. Genheden,et al.  The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities , 2015, Expert opinion on drug discovery.

[38]  P. Saltiel,et al.  Major depressive disorder: mechanism-based prescribing for personalized medicine , 2015, Neuropsychiatric disease and treatment.

[39]  T. Dinan,et al.  Faster, better, stronger: towards new antidepressant therapeutic strategies. , 2015, European journal of pharmacology.

[40]  S. Durgam,et al.  Vilazodone in patients with generalized anxiety disorder: a double-blind, randomized, placebo-controlled, flexible-dose study , 2015, International clinical psychopharmacology.

[41]  M. Thase,et al.  A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, FIXED-DOSE PHASE III STUDY OF VILAZODONE IN PATIENTS WITH GENERALIZED ANXIETY DISORDER , 2015, Depression and anxiety.

[42]  P. L. McCormack.  Vilazodone: A Review in Major Depressive Disorder in Adults , 2015, Drugs.

[43]  A. Montejo,et al.  Sexual side-effects of antidepressant and antipsychotic drugs , 2015, Current opinion in psychiatry.

[44]  C. Gommoll,et al.  Efficacy and safety of vilazodone 20 and 40 mg in major depressive disorder: a randomized, double-blind, placebo-controlled trial , 2015, International clinical psychopharmacology.

[45]  S. Sinning,et al.  Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter. , 2016, Bioorganic & medicinal chemistry.

[46]  Ligen Shi,et al.  Efficacy and tolerability of vilazodone for major depressive disorder: evidence from phase III/IV randomized controlled trials , 2016, Drug design, development and therapy.

[47]  L. Citrome.  Vortioxetine for major depressive disorder: An indirect comparison with duloxetine, escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, using number needed to treat, number needed to harm, and likelihood to be helped or harmed. , 2016, Journal of affective disorders.

[48]  A. Carvalho,et al.  The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature , 2016, Psychotherapy and Psychosomatics.

[49]  P. Masand,et al.  Vilazodone for the Treatment of Depression: An Update , 2016, Chonnam medical journal.

[50]  E. Gouaux,et al.  X-ray structures and mechanism of the human serotonin transporter , 2016, Nature.

[51]  Feng Zhu,et al.  Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study , 2016, Scientific Reports.

[52]  F. Tarazi,et al.  The Preclinical and Clinical Effects of Vilazodone for the Treatment of Major Depressive Disorder , 2016, Expert opinion on drug discovery.

[53]  D. Sheehan,et al.  Efficacy and Safety of Vilazodone in Patients With Generalized Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial. , 2016, The Journal of clinical psychiatry.

[54]  Feng Zhu,et al.  Identification of the inhibitory mechanism of FDA approved selective serotonin reuptake inhibitors: an insight from molecular dynamics simulation study. , 2016, Physical chemistry chemical physics : PCCP.

[55]  K. Bogeso,et al.  Structure–activity relationship studies of citalopram derivatives: examining substituents conferring selectivity for the allosteric site in the 5‐HT transporter , 2016, British journal of pharmacology.

[56]  K. Bogeso,et al.  Exploration of insights, opportunities and caveats provided by the X-ray structures of hSERT. , 2016, Bioorganic & medicinal chemistry letters.

[57]  Bo Li,et al.  NOREVA: normalization and evaluation of MS-based metabolomics data , 2017, Nucleic Acids Res..

[58]  S. Chaki.  mGlu2/3 Receptor Antagonists as Novel Antidepressants. , 2017, Trends in pharmacological sciences.

[59]  Ismail Erol,et al.  Identification of novel serotonin reuptake inhibitors targeting central and allosteric binding sites: A virtual screening and molecular dynamics simulations study. , 2017, Journal of molecular graphics & modelling.

[60]  Feng Zhu,et al.  Differentiating physicochemical properties between NDRIs and sNRIs clinically important for the treatment of ADHD. , 2017, Biochimica et biophysica acta. General subjects.

[61]  M. Thase,et al.  Effects of vilazodone on suicidal ideation and behavior in adults with major depressive disorder or generalized anxiety disorder: post-hoc analysis of randomized, double-blind, placebo-controlled trials , 2017, International clinical psychopharmacology.

[62]  X-ray structure based evaluation of analogs of citalopram: Compounds with increased affinity and selectivity compared with R-citalopram for the allosteric site (S2) on hSERT. , 2017, Bioorganic & medicinal chemistry letters.

[63]  Feng Zhu,et al.  Revealing vilazodone's binding mechanism underlying its partial agonism to the 5-HT1A receptor in the treatment of major depressive disorder. , 2017, Physical chemistry chemical physics : PCCP.

[64]  Jian Li,et al.  Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation. , 2017, ACS chemical neuroscience.

[65]  Jacob Andersen,et al.  Mapping the Binding Site for Escitalopram and Paroxetine in the Human Serotonin Transporter Using Genetically Encoded Photo-Cross-Linkers. , 2017, ACS chemical biology.

[66]  Tingting Fu,et al.  Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics , 2017, Nucleic Acids Res..

[67]  Didier Rognan,et al.  IChem: A Versatile Toolkit for Detecting, Comparing, and Predicting Protein–Ligand Interactions , 2017, ChemMedChem.

[68]  Feng Zhu,et al.  Computational characterization of the selective inhibition of human norepinephrine and serotonin transporters by an escitalopram scaffold. , 2018, Physical chemistry chemical physics : PCCP.

[69]  Yuzong Chen,et al.  What Contributes to Serotonin-Norepinephrine Reuptake Inhibitors' Dual-Targeting Mechanism? The Key Role of Transmembrane Domain 6 in Human Serotonin and Norepinephrine Transporters Revealed by Molecular Dynamics Simulation. , 2018, ACS chemical neuroscience.

[70]  Feng Zhu,et al.  Recent Advances and Challenges of the Drugs Acting on Monoamine Transporters. , 2018, Current medicinal chemistry.

[71]  Christopher Southan,et al.  Caveat Usor: Assessing Differences between Major Chemistry Databases , 2018, ChemMedChem.

[72]  G. Gartlehner,et al.  Efficacy and safety of levomilnacipran, vilazodone and vortioxetine compared with other second-generation antidepressants for major depressive disorder in adults: A systematic review and network meta-analysis. , 2018, Journal of affective disorders.

[73]  E. Gouaux,et al.  Structural basis for recognition of diverse antidepressants by the human serotonin transporter , 2017, Nature Structural & Molecular Biology.

[74]  E. Coccaro.  New Hope for Patients with Major Depressive Disorder? , 2019, The New England journal of medicine.

[75]  Feng Zhu,et al.  How Does Chirality Determine the Selective Inhibition of Histone Deacetylase 6? A Lesson from Trichostatin A Enantiomers Based on Molecular Dynamics. , 2019, ACS chemical neuroscience.

[76]  W. Drevets,et al.  The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder , 2019, Translational Psychiatry.

[77]  Feng Zhu,et al.  Simultaneous Improvement in the Precision, Accuracy, and Robustness of Label-free Proteome Quantification by Optimizing Data Manipulation Chains* , 2019, Molecular & Cellular Proteomics.

[78]  Lixia Yao,et al.  Simultaneous Improvement in the Precision, Accuracy, and Robustness of Label-free Proteome Quantification by Optimizing Data Manipulation Chains. , 2019, Molecular & cellular proteomics : MCP.

[79]  Junmei Wang,et al.  End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design. , 2019, Chemical reviews.

[80]  E. Giltay,et al.  Evaluation of vilazodone for the treatment of depressive and anxiety disorders , 2018, Expert opinion on pharmacotherapy.

[81]  Feng Zhu,et al.  VARIDT 1.0: variability of drug transporter database , 2019, Nucleic Acids Res..

[82]  Xiaofeng Li,et al.  Consistent gene signature of schizophrenia identified by a novel feature selection strategy from comprehensive sets of transcriptomic data , 2019, Briefings Bioinform..

[83]  Feng Zhu,et al.  Clinical trials, progression-speed differentiating features and swiftness rule of the innovative targets of first-in-class drugs , 2019, Briefings Bioinform..

[84]  Xiaofeng Li,et al.  ANPELA: analysis and performance assessment of the label-free quantification workflow for metaproteomic studies , 2019, Briefings Bioinform..