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

Möller-Acuña P, Contreras-Riquelme JS, Rojas-Fuentes C, Nuñez-Vivanco G, Alzate-Morales J, Iturriaga-Vásquez P, Arias HR, Reyes-Parada M - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


RMSD behavior of SB-206553 docked in each one of the three putative binding sites from the α7 nAChR.RMSD values are shown for the compound when bound at: the extracellular domain (ECD; black line), the M2-M3 loop (red line), and the transmembrane domain (TMD; blue line).
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pone.0134444.g007: RMSD behavior of SB-206553 docked in each one of the three putative binding sites from the α7 nAChR.RMSD values are shown for the compound when bound at: the extracellular domain (ECD; black line), the M2-M3 loop (red line), and the transmembrane domain (TMD; blue line).

Mentions: Fig 7 shows the movement of SB-206553 during the 10-ns MD simulation, at each one of the potential binding sites of the α7 nAChR. In the site located in the α7 nAChR-ECD, SB-206553 remained relatively stable (in the same position) during the whole MD simulation. Conversely, the complexes were clearly less stable in the cases in which the drug was bound to either the M2-M3 region or the TMD. These results suggest that the most likely binding site for SB-206553 at the α7 nAChR is the allosteric site located in the ECD. It should be noted that this site is located in a position that roughly coincides with the “vestibule pocket”, an allosteric site identified in a recent crystallographic study that used a chimera of the α7 nAChR and AChBP as a model for the ECD of the α7 nAChR [54].


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

Möller-Acuña P, Contreras-Riquelme JS, Rojas-Fuentes C, Nuñez-Vivanco G, Alzate-Morales J, Iturriaga-Vásquez P, Arias HR, Reyes-Parada M - PLoS ONE (2015)

RMSD behavior of SB-206553 docked in each one of the three putative binding sites from the α7 nAChR.RMSD values are shown for the compound when bound at: the extracellular domain (ECD; black line), the M2-M3 loop (red line), and the transmembrane domain (TMD; blue line).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526571&req=5

pone.0134444.g007: RMSD behavior of SB-206553 docked in each one of the three putative binding sites from the α7 nAChR.RMSD values are shown for the compound when bound at: the extracellular domain (ECD; black line), the M2-M3 loop (red line), and the transmembrane domain (TMD; blue line).
Mentions: Fig 7 shows the movement of SB-206553 during the 10-ns MD simulation, at each one of the potential binding sites of the α7 nAChR. In the site located in the α7 nAChR-ECD, SB-206553 remained relatively stable (in the same position) during the whole MD simulation. Conversely, the complexes were clearly less stable in the cases in which the drug was bound to either the M2-M3 region or the TMD. These results suggest that the most likely binding site for SB-206553 at the α7 nAChR is the allosteric site located in the ECD. It should be noted that this site is located in a position that roughly coincides with the “vestibule pocket”, an allosteric site identified in a recent crystallographic study that used a chimera of the α7 nAChR and AChBP as a model for the ECD of the α7 nAChR [54].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.