A computational study of somatostatin subtype-4 receptor agonist binding

Abstract

The somatostatin subtype-4 receptor (sst4) is highly expressed in neocortical and hippocampal areas, which are affected by amyloid beta accumulation. Sst4 agonists enhance downstream activity of amyloid beta peptide catabolism through neprilysin and may slow the progression of Alzheimer’s disease (AD). Sst4 is a G protein coupled receptor (GPCR), the structure of which has yet to be resolved. A newly constructed sst4 homology model, along with a previously reported model-built sst4 receptor structure, were used in the present study to gain insights into binding requirements of sst4 agonists employing a set of compounds patented by Boehringer Ingelheim. Besides aiming at delineating binding at the macromolecular level of these recently disclosed compounds, our objectives included the generation of a quantitative structure-activity relationship (QSAR) global model to explore the relationship between chemical structure and affinity. Through the implementation of model building, docking, and QSAR, plausible correlations between structural properties and the binding affinity are established. This study sheds light on understanding binding requirements at the sst4 receptor. Graphical abstract: [Figure not available: see fulltext.]