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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.


Common structure of the SB-206553 binding site of the 5-HT2Rs and α7 nAChR.The cavity observed in the site is depicted as a transparent surface with residues in licorice format. Each color represents the chemical nature of residues (polar = green, non-polar = grey, negatively charged = red, positively charged = blue).
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pone.0134444.g010: Common structure of the SB-206553 binding site of the 5-HT2Rs and α7 nAChR.The cavity observed in the site is depicted as a transparent surface with residues in licorice format. Each color represents the chemical nature of residues (polar = green, non-polar = grey, negatively charged = red, positively charged = blue).

Mentions: After the alignment of the SB-206553 binding sites at the 5-HT2Rs and α7 nAChR, a consensus binding site was generated (Fig 10). This three-dimensional pattern contains the residues which are likely responsible for the binding of the drug to the different targets. The consensus binding site is a hydrophobic pocket in which three aromatic residues play a crucial role to establish π-π and/or hydrophobic interactions with the ligand’s indole group, in agreement with our previous simulation. The importance of aromatic interactions for the binding of different ligands at 5-HT2Rs has been documented before [33,43–45]. Importantly, our results show that a similar three-dimensional arrangement is also present in an allosteric site in the α7 nAChR.


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)

Common structure of the SB-206553 binding site of the 5-HT2Rs and α7 nAChR.The cavity observed in the site is depicted as a transparent surface with residues in licorice format. Each color represents the chemical nature of residues (polar = green, non-polar = grey, negatively charged = red, positively charged = blue).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134444.g010: Common structure of the SB-206553 binding site of the 5-HT2Rs and α7 nAChR.The cavity observed in the site is depicted as a transparent surface with residues in licorice format. Each color represents the chemical nature of residues (polar = green, non-polar = grey, negatively charged = red, positively charged = blue).
Mentions: After the alignment of the SB-206553 binding sites at the 5-HT2Rs and α7 nAChR, a consensus binding site was generated (Fig 10). This three-dimensional pattern contains the residues which are likely responsible for the binding of the drug to the different targets. The consensus binding site is a hydrophobic pocket in which three aromatic residues play a crucial role to establish π-π and/or hydrophobic interactions with the ligand’s indole group, in agreement with our previous simulation. The importance of aromatic interactions for the binding of different ligands at 5-HT2Rs has been documented before [33,43–45]. Importantly, our results show that a similar three-dimensional arrangement is also present in an allosteric site in the α7 nAChR.

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.