Investigating The Binding Pocket of Iloprost and Selexipag in The Homology Model of IP Receptor

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease affecting the lung vascular system. It is characterised by an increase in peripheral arteriole pressure leading to respiratory constriction. This causes many symptoms such as hypoxia and heart ventricular failure. The Food and Drug Administration has already approved various interventions to minimise PAH symptoms and to reduce the risk of further complications and death. Iloprost and selexipag are effective interventions to treat PAH patients. Iloprost's mechanism of action is to bind to the prostacyclin (IP) receptor, a type of G-protein coupled receptor (GPCR). Although iloprost is a potent agonist of IP receptors and selexipag is only a partial agonist, the half-life of iloprost presents an obstacle to the patient's treatment because the medication needs to be taken 6-12 times per day. In this project, iloprost and selexipag will be docked into the homology model of the IP receptor to find the receptor binding site of both drugs. This could potentially allow us to resolve why two drugs differ in their potencies and why iloprost is less efficacious than selexipag. Finding a new binding site in the pocket of the IP receptor would fill a knowledge gap in the literature and advance drug development and discovery in this area. The experimental strategy is to build a homology model of the IP receptor using advanced computer software like (SWISS-MODEL and GalaxyWEB) and online Protein Data Bases, which provide a wide range of protein amino acid sequences for similar receptors. Hence, it is possible to draw and generate a receptor's crystal structure in a 3D form to be docked by the drug ligand.