title: Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile.
abstract: Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simultaneously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds is a difficult task, particularly when the drugs are aimed to act at receptors with diverse structure, function and endogenous ligand. In the present work, using docking and molecular dynamics methodologies, we established the most probable binding sites of SB-206553, a drug originally described as a competitive antagonist of serotonin type 2B/2C metabotropic receptors (5-HT2B/2CRs) and more recently as a positive allosteric modulator of the ionotropic α7 nicotinic acetylcholine receptor (nAChR). To this end, we employed the crystal structures of the 5-HT2BR and acetylcholine binding protein as templates to build homology models of the 5-HT2CR and α7 nAChR, respectively. Then, using a statistical algorithm, the similarity between these binding sites was determined. Our analysis showed that the most plausible binding sites for SB-206553 at 5-HT2Rs and α7 nAChR are remarkably similar, both in size and chemical nature of the amino acid residues lining these pockets, thus providing a rationale to explain its affinity towards both receptor types. Finally, using a computational tool for multiple binding site alignment, we determined a consensus binding site, which should be useful for the rational design of novel compounds acting simultaneously at these two types of highly different protein targets.
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile; Programa de Doctorado en Biotecnología, Universidad de Santiago de Chile, Santiago, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: Möller-Acuña
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile; Laboratorio de Biología Computacional, Fundación Ciencia & Vida, Santiago, Chile.
authors.forename: J Sebastián
authors.initials: JS
authors.lastname: Contreras-Riquelme
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rojas-Fuentes
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez-Vivanco
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
authors.forename: Jans
authors.initials: J
authors.lastname: Alzate-Morales
authors.affiliation: Facultad de Ingeniería y Ciencias, Universidad de la Frontera, Temuco, Chile.
authors.forename: Patricio
authors.initials: P
authors.lastname: Iturriaga-Vásquez
authors.affiliation: Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA, United States of America.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.affiliation: Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile; Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile.
authors.forename: Miguel
authors.initials: M
authors.lastname: Reyes-Parada
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D044348:Receptors, Serotonin, 5-HT2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012702:Serotonin Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D007211:Indoles; D020033:Protein Isoforms; D011725:Pyridines; D044348:Receptors, Serotonin, 5-HT2; D012702:Serotonin Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; C094868:SB 206553