Similarities between the binding sites of SB-206553 at serotonin type 2 and alpha7 acetylcholine nicotinic receptors: Rationale for its polypharmacological profile

Patricia Möller-Acuña, J. Sebastián Contreras-Riquelme, Cecilia Rojas-Fuentes, Gabriel Nuñez-Vivanco, Jans Alzate-Morales, Patricio Iturriaga-Vásquez, Hugo R. Arias, Miguel Reyes-Parada

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Article numbere0134444
JournalPLoS ONE
Volume10
Issue number8
DOIs
StatePublished - 5 Aug 2015
Externally publishedYes

Fingerprint

alpha7 Nicotinic Acetylcholine Receptor
acetylcholine
serotonin
binding sites
Serotonin
Binding Sites
cholinergic receptors
Nicotinic Receptors
receptors
drugs
Pharmaceutical Preparations
Polypharmacology
Receptor, Serotonin, 5-HT2B
Serotonin Antagonists
Systems Biology
molecular dynamics
Molecular Dynamics Simulation
crystal structure
Linings
Modulators

Cite this

Möller-Acuña, P., Contreras-Riquelme, J. S., Rojas-Fuentes, C., Nuñez-Vivanco, G., Alzate-Morales, J., Iturriaga-Vásquez, P., ... Reyes-Parada, M. (2015). Similarities between the binding sites of SB-206553 at serotonin type 2 and alpha7 acetylcholine nicotinic receptors: Rationale for its polypharmacological profile. PLoS ONE, 10(8), [e0134444]. https://doi.org/10.1371/journal.pone.0134444
Möller-Acuña, Patricia ; Contreras-Riquelme, J. Sebastián ; Rojas-Fuentes, Cecilia ; Nuñez-Vivanco, Gabriel ; Alzate-Morales, Jans ; Iturriaga-Vásquez, Patricio ; Arias, Hugo R. ; Reyes-Parada, Miguel. / Similarities between the binding sites of SB-206553 at serotonin type 2 and alpha7 acetylcholine nicotinic receptors : Rationale for its polypharmacological profile. In: PLoS ONE. 2015 ; Vol. 10, No. 8.
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Möller-Acuña, P, Contreras-Riquelme, JS, Rojas-Fuentes, C, Nuñez-Vivanco, G, Alzate-Morales, J, Iturriaga-Vásquez, P, Arias, HR & Reyes-Parada, M 2015, 'Similarities between the binding sites of SB-206553 at serotonin type 2 and alpha7 acetylcholine nicotinic receptors: Rationale for its polypharmacological profile', PLoS ONE, vol. 10, no. 8, e0134444. https://doi.org/10.1371/journal.pone.0134444

Similarities between the binding sites of SB-206553 at serotonin type 2 and alpha7 acetylcholine nicotinic receptors : Rationale for its polypharmacological profile. / Möller-Acuña, Patricia; Contreras-Riquelme, J. Sebastián; Rojas-Fuentes, Cecilia; Nuñez-Vivanco, Gabriel; Alzate-Morales, Jans; Iturriaga-Vásquez, Patricio; Arias, Hugo R.; Reyes-Parada, Miguel.

In: PLoS ONE, Vol. 10, No. 8, e0134444, 05.08.2015.

Research output: Contribution to journalArticle

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AU - Möller-Acuña, Patricia

AU - Contreras-Riquelme, J. Sebastián

AU - Rojas-Fuentes, Cecilia

AU - Nuñez-Vivanco, Gabriel

AU - Alzate-Morales, Jans

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Möller-Acuña P, Contreras-Riquelme JS, Rojas-Fuentes C, Nuñez-Vivanco G, Alzate-Morales J, Iturriaga-Vásquez P et al. Similarities between the binding sites of SB-206553 at serotonin type 2 and alpha7 acetylcholine nicotinic receptors: Rationale for its polypharmacological profile. PLoS ONE. 2015 Aug 5;10(8). e0134444. https://doi.org/10.1371/journal.pone.0134444