Discovery of Novel Selective Serotonin Reuptake Inhibitors through Development of a Protein-Based Pharmacophore

The serotonin transporter (SERT), a member of the neurotransmitter sodium symporter (NSS) family, is responsible for the reuptake of serotonin from the synaptic cleft to maintain neurotransmitter homeostasis. SERT is established as an important target in the treatment of anxiety and depression. Because a high-resolution crystal structure is not available, a computational model of SERT was built based upon the X-ray coordinates of the leucine transporter LeuT, a bacterial NSS homologue. The model was used to develop the first SERT structure-based pharmacophore. Virtual screening (VS) of a small molecule structural library using the generated SERT computational model yielded candidate ligands of diverse scaffolds. Pharmacological analysis of the VS hits identified two SERT-selective compounds, potential lead compounds for further SERT-related medication development.

[1]  N. Pattabiraman,et al.  “Teaching old drugs to kill new bugs”: structure-based discovery of anti-SARS drugs , 2004, Biochemical and Biophysical Research Communications.

[2]  Brian K. Shoichet,et al.  Virtual screening of chemical libraries , 2004, Nature.

[3]  M. Zvelebil,et al.  Novel inhibitors of Trypanosoma cruzi dihydrofolate reductase. , 2001, European journal of medicinal chemistry.

[4]  M C Nicklaus,et al.  HIV-1 integrase pharmacophore: discovery of inhibitors through three-dimensional database searching. , 1997, Journal of medicinal chemistry.

[5]  R J Fletterick,et al.  Structure-based design of parasitic protease inhibitors. , 1996, Bioorganic & medicinal chemistry.

[6]  Harel Weinstein,et al.  A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na+ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function , 2006, Molecular Pharmacology.

[7]  G Folkers,et al.  A new pharmophoric model for 5-HT reuptake-inhibitors: differentiation of amphetamine analogues. , 1994, Pharmaceutica acta Helvetiae.

[8]  O. Taboureau,et al.  Location of the Antidepressant Binding Site in the Serotonin Transporter , 2009, Journal of Biological Chemistry.

[9]  F. Allen.  The Cambridge Structural Database: a quarter of a million crystal structures and rising. , 2002, Acta crystallographica. Section B, Structural science.

[10]  M. Reith,et al.  Antidepressant specificity of serotonin transporter suggested by three LeuT–SSRI structures , 2009, Nature Structural &Molecular Biology.

[11]  E. Bradley,et al.  Performance of 3D-database molecular docking studies into homology models. , 2004, Journal of medicinal chemistry.

[12]  G. Folkers,et al.  Quantitative Structure‐Activity Relationships of Phenyltropanes as Inhibitors of Three Monoamine Transporters: Classical and CoMFA studies , 1999 .

[13]  B. Greenberg,et al.  Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype , 2003, Molecular Psychiatry.

[14]  Rolf Hilgenfeld,et al.  Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs , 2003, Science.

[15]  G. Schneider,et al.  Virtual Screening for Bioactive Molecules , 2000 .

[16]  Michael K. Gilson,et al.  Screening Drug-Like Compounds by Docking to Homology Models: A Systematic Study , 2006, J. Chem. Inf. Model..

[17]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[18]  M. Hamon,et al.  Neurotransmitter transporters in the central nervous system. , 1999, Pharmacological reviews.

[19]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.

[20]  Alex M. Clark,et al.  2D Depiction of Protein—Ligand Complexes. , 2007 .

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

[22]  Jeffry D Madura,et al.  Dopamine transporter comparative molecular modeling and binding site prediction using the LeuTAa leucine transporter as a template , 2008, Proteins.

[23]  P Manivet,et al.  Definition of an uptake pharmacophore of the serotonin transporter through 3D-QSAR analysis. , 2005, Current medicinal chemistry.

[24]  P. Kollman,et al.  How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? , 2000 .

[25]  I. Enyedy,et al.  Structure-based approach for the discovery of bis-benzamidines as novel inhibitors of matriptase. , 2001, Journal of medicinal chemistry.

[26]  Sean Ekins,et al.  Pharmacophore-based discovery of ligands for drug transporters. , 2006, Advanced drug delivery reviews.

[27]  S. Amara,et al.  Neurotransmitter transporters: recent progress. , 1993, Annual review of neuroscience.

[28]  Somesh D. Sharma,et al.  Managing protein flexibility in docking and its applications. , 2009, Drug discovery today.

[29]  Alan Frazer,et al.  Pharmacology of antidepressants. , 1997, Journal of clinical psychopharmacology.

[30]  Laura M. Geffert,et al.  Identification of a novel selective serotonin reuptake inhibitor by coupling monoamine transporter-based virtual screening and rational molecular hybridization. , 2011, ACS chemical neuroscience.

[31]  A. Sali,et al.  Large-scale protein structure modeling of the Saccharomyces cerevisiae genome. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Eric Gouaux,et al.  A Competitive Inhibitor Traps LeuT in an Open-to-Out Conformation , 2008, Science.

[33]  J. Ponder,et al.  Force fields for protein simulations. , 2003, Advances in protein chemistry.

[34]  Da-Neng Wang,et al.  LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake , 2007, Science.

[35]  S L Lin,et al.  Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods. , 1997, Journal of medicinal chemistry.

[36]  Bob McMeeking,et al.  The United Kingdom Chemical Database Service: CDS , 2004 .

[37]  R. Goldberg,et al.  Selective serotonin reuptake inhibitors: infrequent medical adverse effects. , 1998, Archives of family medicine.

[38]  J. Ferguson.  SSRI Antidepressant Medications: Adverse Effects and Tolerability. , 2001, Primary care companion to the Journal of clinical psychiatry.

[39]  J. Madura,et al.  Receptor-Based Discovery of a Plasmalemmal Monoamine Transporter Inhibitor via High Throughput Docking and Pharmacophore Modeling. , 2010, ACS chemical neuroscience.

[40]  E. Richelson,et al.  Binding of antidepressants to human brain receptors: focus on newer generation compounds , 1994, Psychopharmacology.

[41]  I. Enyedy,et al.  Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. , 2001, Journal of medicinal chemistry.

[42]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[43]  R. Blakely,et al.  Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders , 2002, The Pharmacogenomics Journal.

[44]  Christopher K Surratt,et al.  Dissociation of high-affinity cocaine analog binding and dopamine uptake inhibition at the dopamine transporter. , 2003, Molecular pharmacology.

[45]  A. Lesk,et al.  The relation between the divergence of sequence and structure in proteins. , 1986, The EMBO journal.

[46]  J. Irwin,et al.  ZINC ? A Free Database of Commercially Available Compounds for Virtual Screening. , 2005 .

[47]  M. Novak,et al.  Single nucleotide polymorphisms distinguish multiple dopamine transporter alleles in primates: implications for association with attention deficit hyperactivity disorder and other neuropsychiatric disorders , 2001, Molecular Psychiatry.

[48]  I. Enyedy,et al.  Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies. , 2000, Journal of medicinal chemistry.

[49]  Aloke K. Dutta,et al.  Three-dimensional quantitative structure-activity relationship (3D QSAR) and pharmacophore elucidation of tetrahydropyran derivatives as serotonin and norepinephrine transporter inhibitors , 2008, J. Comput. Aided Mol. Des..

[50]  Jonathan A. Javitch,et al.  Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation , 2009, Proceedings of the National Academy of Sciences.

[51]  T. Halgren.  Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[52]  A. Newman,et al.  Recognition of Benztropine by the Dopamine Transporter (DAT) Differs from That of the Classical Dopamine Uptake Inhibitors Cocaine, Methylphenidate, and Mazindol as a Function of a DAT Transmembrane 1 Aspartic Acid Residue , 2005, Journal of Pharmacology and Experimental Therapeutics.

[53]  R. Griffith,et al.  Pharmacophore design and database searching for selective monoamine neurotransmitter transporter ligands. , 2008, Journal of molecular graphics & modelling.

[54]  D W Zaharevitz,et al.  The discovery of novel, structurally diverse protein kinase C agonists through computer 3D-database pharmacophore search. Molecular modeling studies. , 1994, Journal of medicinal chemistry.

[55]  Eva M. Krovat,et al.  Synthesis and Molecular Modeling of New 1-Aryl-3-[4-arylpiperazin-1-yl]-1-propane Derivatives with High Affinity at the Serotonin Transporter and at 5-HT1A Receptors , 2002 .

[56]  H. Meltzer,et al.  Reduced Levels of Norepinephrine Transporters in the Locus Coeruleus in Major Depression , 1997, The Journal of Neuroscience.

[57]  Y. Martin,et al.  3D database searching in drug design. , 1992, Journal of medicinal chemistry.

[58]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[59]  Harvey Rubin,et al.  Cysteine proteinases from distinct cellular compartments are recruited to phagocytic vesicles by Entamoeba histolytica. , 2002, Molecular and biochemical parasitology.

[60]  R. Blakely,et al.  Familial Orthostatic Tachycardia Due to Norepinephrine Transporter Deficiency , 2001, Annals of the New York Academy of Sciences.

[61]  J. Madura,et al.  Family 18 chitinase-oligosaccharide substrate interaction: subsite preference and anomer selectivity of Serratia marcescens chitinase A. , 2003, The Biochemical journal.

[62]  J. Deschamps,et al.  Further structural exploration of trisubstituted asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their corresponding disubstituted (3S,6S) pyran derivatives: a proposed pharmacophore model for high-affinity interaction with the dopamine, serotonin, and nor , 2006, Journal of medicinal chemistry.

[63]  Eric Beitz,et al.  TeXshade: shading and labeling of multiple sequence alignments using LaTeX2e , 2000, Bioinform..

[64]  Yvonne C. Martin,et al.  A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists , 1993, J. Comput. Aided Mol. Des..

[65]  Eric Gouaux,et al.  Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters , 2005, Nature.

[66]  F E Cohen,et al.  Leishmania major: molecular modeling of cysteine proteases and prediction of new nonpeptide inhibitors. , 1997, Experimental parasitology.

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

[68]  Eric Gouaux,et al.  Antidepressant binding site in a bacterial homologue of neurotransmitter transporters , 2007, Nature.

[69]  J. Green,et al.  Tricyclic antidepressant drugs block histamine H2 receptor in brain , 1977, Nature.

[70]  G. Rudnick.  Mechanisms of Biogenic Amine Neurotransmitter Transporters , 2002 .

[71]  A. Sali,et al.  Statistical potential for assessment and prediction of protein structures , 2006, Protein science : a publication of the Protein Society.

[72]  N. Nelson,et al.  The Family of Na+/Cl− Neurotransmitter Transporters , 1998, Journal of neurochemistry.