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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.


Structural determinants of the SB-206553 binding site at the 5-HT2Rs.(A) Ribbon diagram of the superimposed structures of the 5-HT2BR (silver) and 5-HT2CR (purple), showing the putative binding site for SB-206553 (red or blue, respectively) at each protein. For comparative purposes, the binding site for ergotamine (yellow) in the crystal structure of the 5-HT2BR (PDB code 4IB4) is also depicted. (B-C) Close ups of the docking poses of SB-206553 at 5-HT2BR and 5-HT2CR, respectively. Main active site amino acid residues (cyan) are rendered as stick models.
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pone.0134444.g005: Structural determinants of the SB-206553 binding site at the 5-HT2Rs.(A) Ribbon diagram of the superimposed structures of the 5-HT2BR (silver) and 5-HT2CR (purple), showing the putative binding site for SB-206553 (red or blue, respectively) at each protein. For comparative purposes, the binding site for ergotamine (yellow) in the crystal structure of the 5-HT2BR (PDB code 4IB4) is also depicted. (B-C) Close ups of the docking poses of SB-206553 at 5-HT2BR and 5-HT2CR, respectively. Main active site amino acid residues (cyan) are rendered as stick models.

Mentions: Fig 5A shows a general view for the most stable docking poses for SB-206553 when docked at either the 5-HT2BR or 5-HT2CR. The docking analysis of 150 simulations for each drug-receptor complex, revealed a total of five and seven multimember conformation clusters at the 5-HT2BR and 5-HT2CR, respectively (S4 and S5 Figs). In both cases, the configuration with the lowest binding energy (-17.2 kcal/mol and -15.3 kcal/mol, respectively) was a member of the highest populated cluster (S4 and S5 Figs). The models show that the drug docks in a very similar pose at both targets. Moreover, this binding site is located in a position analogous to that occupied by the agonist ergotamine in the crystal structure of the 5-HT2BR [12]. This result agrees with the competitive nature of the action of SB-206553 [7]. When these ligand-receptor complexes were submitted to 10-ns MD simulations, almost no changes were observed in the position adopted by SB-206553 at its binding sites (RMSD < 0.4 Å during the whole simulations). Furthermore, this site coincides with the binding pocket described for 5-HT and a series of 5-HT2CR antagonists and inverse agonists, as defined by a similar docking protocol as that used in the present work [33]. These observations support the plausibility of this location as the most probable binding site for SB-206553 at 5-HT2Rs.


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)

Structural determinants of the SB-206553 binding site at the 5-HT2Rs.(A) Ribbon diagram of the superimposed structures of the 5-HT2BR (silver) and 5-HT2CR (purple), showing the putative binding site for SB-206553 (red or blue, respectively) at each protein. For comparative purposes, the binding site for ergotamine (yellow) in the crystal structure of the 5-HT2BR (PDB code 4IB4) is also depicted. (B-C) Close ups of the docking poses of SB-206553 at 5-HT2BR and 5-HT2CR, respectively. Main active site amino acid residues (cyan) are rendered as stick models.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134444.g005: Structural determinants of the SB-206553 binding site at the 5-HT2Rs.(A) Ribbon diagram of the superimposed structures of the 5-HT2BR (silver) and 5-HT2CR (purple), showing the putative binding site for SB-206553 (red or blue, respectively) at each protein. For comparative purposes, the binding site for ergotamine (yellow) in the crystal structure of the 5-HT2BR (PDB code 4IB4) is also depicted. (B-C) Close ups of the docking poses of SB-206553 at 5-HT2BR and 5-HT2CR, respectively. Main active site amino acid residues (cyan) are rendered as stick models.
Mentions: Fig 5A shows a general view for the most stable docking poses for SB-206553 when docked at either the 5-HT2BR or 5-HT2CR. The docking analysis of 150 simulations for each drug-receptor complex, revealed a total of five and seven multimember conformation clusters at the 5-HT2BR and 5-HT2CR, respectively (S4 and S5 Figs). In both cases, the configuration with the lowest binding energy (-17.2 kcal/mol and -15.3 kcal/mol, respectively) was a member of the highest populated cluster (S4 and S5 Figs). The models show that the drug docks in a very similar pose at both targets. Moreover, this binding site is located in a position analogous to that occupied by the agonist ergotamine in the crystal structure of the 5-HT2BR [12]. This result agrees with the competitive nature of the action of SB-206553 [7]. When these ligand-receptor complexes were submitted to 10-ns MD simulations, almost no changes were observed in the position adopted by SB-206553 at its binding sites (RMSD < 0.4 Å during the whole simulations). Furthermore, this site coincides with the binding pocket described for 5-HT and a series of 5-HT2CR antagonists and inverse agonists, as defined by a similar docking protocol as that used in the present work [33]. These observations support the plausibility of this location as the most probable binding site for SB-206553 at 5-HT2Rs.

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.