The development and validation of a novel virtual screening cascade protocol to identify potential serotonin 5-HT(7)R antagonists.

In an attempt to identify new ligands for the 5-HT(7) receptor (5-HT(7)R), we developed and tested a hierarchical multi-step strategy of virtual screening (VS) based on two-dimensional (2D) pharmacophore similarity, physicochemical scalar descriptors, an ADME/Tox filter, three-dimensional (3D) pharmacophore searches and a docking protocol. Six chemical classes of 5-HT(7)R antagonists were used as query structures in a double-path virtual screening scheme. The Enamine screening database, consisting of approximately 730,000 commercially available drug-like compounds, was adopted and used as a source of structures. A biological evaluation of 26 finally selected virtual hits resulted in finding two benzodioxane derivatives with significant affinity (K(i)=197 and 265 nM). The approach described in this case study can be easily used as a general rational drug design tool for other biological targets.

[1]  V. A. Davis,et al.  Cyclic AMP mediates circadian phase shifts induced by microinjection of serotonergic drugs in the hamster dorsal raphe nucleus , 2005, Brain Research.

[2]  Alexandre Varnek,et al.  Chemoinformatics approaches to virtual screening , 2008 .

[3]  Ferran Sanz,et al.  Multistructure 3D-QSAR studies on a series of conformationally constrained butyrophenones docked into a new homology model of the 5-HT2A receptor. , 2007, Journal of medicinal chemistry.

[4]  R. Jakus,et al.  Selective 5-HT1A and 5-HT7 antagonists decrease epileptic activity in the WAG/Rij rat model of absence epilepsy , 2004, Neuroscience Letters.

[5]  D. Sibley,et al.  Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. , 1993, The Journal of biological chemistry.

[6]  G. Klebe,et al.  Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. , 2004, Journal of medicinal chemistry.

[7]  R. Eglen,et al.  Characterization of putative 5‐ht7 receptors mediating direct relaxation in Cynomolgus monkey isolated jugular vein , 1996, British journal of pharmacology.

[8]  Andreas Evers,et al.  Virtual screening of biogenic amine-binding G-protein coupled receptors: comparative evaluation of protein- and ligand-based virtual screening protocols. , 2005, Journal of medicinal chemistry.

[9]  M. Nowak,et al.  Homology modeling of the serotonin 5-HT1A receptor using automated docking of bioactive compounds with defined geometry. , 2006, Journal of medicinal chemistry.

[10]  Mateusz Nowak,et al.  Receptor-based pharmacophores for serotonin 5-HT7R antagonists-implications to selectivity. , 2006, Journal of medicinal chemistry.

[11]  H. Vaudry,et al.  Phenylpyrroles, a new chemolibrary virtual screening class of 5-HT7 receptor ligands. , 2005, Bioorganic & medicinal chemistry letters.

[12]  M. Ikeda,et al.  Positive Association of the Serotonin 5-HT7 Receptor Gene with Schizophrenia in a Japanese Population , 2006, Neuropsychopharmacology.

[13]  A. Dogrul,et al.  Systemic morphine produce antinociception mediated by spinal 5‐HT7, but not 5‐HT1A and 5‐HT2 receptors in the spinal cord , 2006, British journal of pharmacology.

[14]  T. Branchek,et al.  Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. , 1993, The Journal of biological chemistry.

[15]  E. Kellenberger,et al.  Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening. , 2007, Journal of medicinal chemistry.

[16]  J. Terrón,et al.  Is the 5-HT(7) receptor involved in the pathogenesis and prophylactic treatment of migraine? , 2002, European journal of pharmacology.

[17]  P. Hedlund.  The 5-HT7 receptor and disorders of the nervous system: an overview , 2009, Psychopharmacology.

[18]  G. Mcallister,et al.  The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor , 2003, Neuropharmacology.

[19]  A. Meneses.  Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task , 2004, Behavioural Brain Research.

[20]  H. van de Waterbeemd,et al.  ADMET in silico modelling: towards prediction paradise? , 2003, Nature reviews. Drug discovery.

[21]  P P Humphrey,et al.  International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). , 1994, Pharmacological reviews.