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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.


Potential binding sites for SB-206553 at the α7 nAChR.Ribbon diagram of the α7 nAChR model showing the putative binding sites for SB-206553 in the extracellular domain (ECD; red), at the M2-M3 loop (orange), and in the transmembrane domain (TMD; blue), respectively. β-Sheets and α-helices are shown in yellow and purple, respectively. The insets show molecular details of the docking poses of SB-206553 at each putative binding site. For comparative purposes, the binding pose of nicotine (green) in the crystal structure of the AChBP (PDB code 1UW6) is also depicted.
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pone.0134444.g006: Potential binding sites for SB-206553 at the α7 nAChR.Ribbon diagram of the α7 nAChR model showing the putative binding sites for SB-206553 in the extracellular domain (ECD; red), at the M2-M3 loop (orange), and in the transmembrane domain (TMD; blue), respectively. β-Sheets and α-helices are shown in yellow and purple, respectively. The insets show molecular details of the docking poses of SB-206553 at each putative binding site. For comparative purposes, the binding pose of nicotine (green) in the crystal structure of the AChBP (PDB code 1UW6) is also depicted.

Mentions: When SB-206553 was docked at both the ECD and TMD of the α7 nAChR, three possible binding sites were detected (Fig 6). The most stable poses (binding energy = -23.8 kcal/mol; S6 Fig) showed the compound docked in a pocket in the ECD, which is different from the orthosteric site occupied by nicotine. Nevertheless, similarly stable complexes (as judged by docking energies; S7 Fig) were detected with the drug bound to sites located in the M2-M3 loop and in the TMD of the α7 nAChR (Fig 6). Thus, after docking of SB-206553 at this region, six multimember conformation clusters were identified, with the two highest populated clusters having 72 (M2-M3 loop) and 68 (TMD) members out of 150 conformations (S7 Fig). The three sites identified have been previously shown to be the binding site (or to modulate the effects) of different positive allosteric modulators (PAMs) [48–53], and therefore any of them might account for the pharmacological effects of SB-206553 at this receptor. Since none of these binding sites could be a priori selected/discarded based on energy criteria or previous data, MD simulations were performed to evaluate the stability of the ligand at each one of the potential binding sites.


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)

Potential binding sites for SB-206553 at the α7 nAChR.Ribbon diagram of the α7 nAChR model showing the putative binding sites for SB-206553 in the extracellular domain (ECD; red), at the M2-M3 loop (orange), and in the transmembrane domain (TMD; blue), respectively. β-Sheets and α-helices are shown in yellow and purple, respectively. The insets show molecular details of the docking poses of SB-206553 at each putative binding site. For comparative purposes, the binding pose of nicotine (green) in the crystal structure of the AChBP (PDB code 1UW6) is also depicted.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134444.g006: Potential binding sites for SB-206553 at the α7 nAChR.Ribbon diagram of the α7 nAChR model showing the putative binding sites for SB-206553 in the extracellular domain (ECD; red), at the M2-M3 loop (orange), and in the transmembrane domain (TMD; blue), respectively. β-Sheets and α-helices are shown in yellow and purple, respectively. The insets show molecular details of the docking poses of SB-206553 at each putative binding site. For comparative purposes, the binding pose of nicotine (green) in the crystal structure of the AChBP (PDB code 1UW6) is also depicted.
Mentions: When SB-206553 was docked at both the ECD and TMD of the α7 nAChR, three possible binding sites were detected (Fig 6). The most stable poses (binding energy = -23.8 kcal/mol; S6 Fig) showed the compound docked in a pocket in the ECD, which is different from the orthosteric site occupied by nicotine. Nevertheless, similarly stable complexes (as judged by docking energies; S7 Fig) were detected with the drug bound to sites located in the M2-M3 loop and in the TMD of the α7 nAChR (Fig 6). Thus, after docking of SB-206553 at this region, six multimember conformation clusters were identified, with the two highest populated clusters having 72 (M2-M3 loop) and 68 (TMD) members out of 150 conformations (S7 Fig). The three sites identified have been previously shown to be the binding site (or to modulate the effects) of different positive allosteric modulators (PAMs) [48–53], and therefore any of them might account for the pharmacological effects of SB-206553 at this receptor. Since none of these binding sites could be a priori selected/discarded based on energy criteria or previous data, MD simulations were performed to evaluate the stability of the ligand at each one of the potential binding sites.

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.