Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile

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.

Synthesis and Docking of Novel 3‐Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5‐HT1AR/SERT

“…The simulation time was sufficient to obtain an equilibrated system (root mean square deviation‐RMSD‐ values <2 Å). All other conditions were as previously described . Docking of compounds, both in the SERT structure and the 5‐HT 1A model, were performed with the AutoDock 4.2 suite , following protocols previously described elsewhere .…”

“…All other conditions were as previously described . Docking of compounds, both in the SERT structure and the 5‐HT 1A model, were performed with the AutoDock 4.2 suite , following protocols previously described elsewhere . The models used in this study were built and validated according to our previous publications .…”

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

“…2) Given the presence of other nAChRs and homologous receptors, high PAM selectivity is required. However, PAMs targeting multiple receptors might show better efficacy Möller-Acuña et al, 2015). 3) Excessive receptor activation, particularly with efficacious nondesensitizing PAMs, might lead to cytotoxicity, which is an issue of concern and controversy (Ng et al, 2007;Liu et al, 2009;Williams et al, 2012;Guerra-Álvarez et al, 2015;Uteshev, 2016).…”

Molecular function of α7 nicotinic receptors as drug targets

“…), and (vi) the fact that PAMs targeting multiple receptors might show better efficacy (Möller‐Acuña et al . ; Iturriaga‐Vásquez et al . ), indicating that for each pathological context their actions at other involved receptors should be tested.…”