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PLoS One. 2015 Aug 5;10(8):e0134444. doi: 10.1371/journal.pone.0134444. eCollection 2015.

Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile.

Author information

1
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.
2
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.
3
Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
4
Facultad de Ingeniería y Ciencias, Universidad de la Frontera, Temuco, Chile.
5
Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA, United States of America.
6
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.

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.

PMID:
26244344
PMCID:
PMC4526571
DOI:
10.1371/journal.pone.0134444
[Indexed for MEDLINE]
Free PMC Article

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