Modeling of interactions between the human 5-HT7 receptor and ligands

Abstract

By constructing homology models of the human 5-HT7 (5-hydroxytryptamin, serotonin) receptor based on three different X-ray crystals of the turkey beta1 adrenergic receptor (one with an agonist complex, one with antagonist complex and one with a partial agonist complex) we tried to determine if there are any difference between the docking of agonists, antagonist and partial agonist ligands in the three different models. The building of the homology models and docking where done using Molsoft ICM pro. X-ray crystal structures where downloaded from the PDB database (www.rcsb.org) and the amino acid sequence from UniProt database (www.uniprot.org). Ligands were selected from was selected from ChEMBL database. Article searches where done in www.pubmed.com. Results did not indicate a difference in ligand-receptor interactions or energy state of the complexes across the agonist and antagonist models. The model based on the partial agonist complex template yielded less successful dockings and higher energy levels of docking complexes. Residues included in the binding site, in trans membrane helix's 3 (Asp3.32), 5 (Thr5.43, Ser5.42, Tyr5.38, Phe5.47), 6 (Phe6.51, Phe6.52, Ser6.55), and 7 (Phe7.38), that interact with the ligands in this study, are in accordance with previously published SAR, docking and mutation papers included in this research. Other residues with repeating interaction with ligands include Val2.60, Val3.33 and Tyr5.38. Further investigation on the role of these amino acids in ligand binding could be useful. Agonists and partial agonists tends to bind in the pocket between helix's 4-7, while the antagonists occupy both the pocket between TMH4-6 and the pocket between TMH7-3.