RESUMO
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.
Assuntos
Indóis/química , Piridinas/química , Receptores 5-HT2 de Serotonina/química , Receptor Nicotínico de Acetilcolina alfa7/química , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Ligação Competitiva , Humanos , Indóis/metabolismo , Indóis/farmacologia , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Estrutura Molecular , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Piridinas/metabolismo , Piridinas/farmacologia , Receptores 5-HT2 de Serotonina/genética , Receptores 5-HT2 de Serotonina/metabolismo , Homologia de Sequência de Aminoácidos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
The anti-inflammatory activity of quercetin was evaluated through serotonin-induced rat-paw edema. The experiments showed that quercetin had an important effect on acute inflammatory processes. Docking of serotonin and quercetin into the homology model of the 5-Hydroxytryptamine Type 2 Receptor allowed to analyze the structural basis of the anti-inflammatory activity. Results showed that serotonin and quercetin bind in the same region of the active site with a similar binding energy but quercetin has a much bigger inhibition constant. Therefore, it seems possible that quercetin may act as a natural inhibitor of the receptor blocking the acute inflammation generated by serotonin.