Molecular modeling of 3D structure of the oxytocin receptor. Discovery of novel oxytocin receptor agonists via molecular docking studies.

Abstract

Oxytocin has been shown to be implicated in psychiatric diseases such as depression, anxiety disorders, autism post-traumatic stress disorder, and schizophrenia. As a result, oxytocin can be used as a potential treatment for these brain disorders. However, oxytocin is a large peptide, and is therefore unable to cross the blood brain barrier. Thus, the development of new small non-peptide drugs would be of great benefit in the treatment of these neurological disorders.

In this study, new non-peptide agonists have been proposed based on homology modeling and virtual ligand screening. There is no available experimentally solved structure of the oxytocin receptor; hence three models are constructed and refined using known 3D crystal structures of evolutionary related proteins (PDB: 2Y00, PDB: 4BVN and PDB: 4LDE). The ability of the three models to discriminate between true ligands and decoys was tested and analyzed using the Receiver operating characteristics (ROC) curve.

A virtual ligand screening procedure was applied on the most suitable of the 3 models (4LDE-based model) in order to identify potential binding compounds that can be used as oxytocin receptor agonists.

The results obtained from this study are 15 compounds, which can be tested in vivo and eventually used as potential drug candidates.