Modeling of the hEP1 receptor based on the crystallographic structure of β2-adrenergic receptor and its assessment with docking studies and molecular dynamics simulation

Abstract

Introduction: The human EP1 (hEP1) prostanoid receptor is a G-Protein Coupled Receptor (GPCR) which plays important physiological roles in some systems in the body like cardiovascular and immune systems and could be a very important target for drug design.

Materials and methods: To understand the molecular structure of hEP1 receptor, a homology model of the receptor was constructed from the 2.4 Å resolution crystal structure of human β2-adrenergic receptor (PDB code: 2RH1), using three different sequence alignments. The model including PGE2 inside the active site was subjected to molecular dynamics simulation. Docking studies were performed for PGE2 and 10 prostanoid analogs in the active site of the modeled receptor.

Results and Discussion: The structure of modeled receptor remained stable during the 10 nanosecond(ns) simulation. In the docking simulations a correlation of r2=0.74 was observed between the Ki values and the docking scores of the prostanoid compounds. The structure which was modeled in the present study can be used in the structure-based drug design, helping the rational design of novel ligands for the hEP1 receptor.