Study of New Oxytocin Antagonist Barusiban (Fe200 440) Affinity Toward Human Oxytocin Receptor Versus Vasopressin V1a and V2 Receptors - Molecular Dynamics Simulation in POPC Bilayer

Abstract

The nonapeptide hormone oxytocin CYIQNCPLG-NH 2 (OT) controls birth, lactation and other physiological functions in the mammals via stimulation of its receptor (OTR), a member of Class A G protein-coupled receptors (GPCRs). OT is structurally akin to arginine vasopressin ([F2,R8]OT, AVP) involved, among other things, in the increase of blood pressure and antidiuresis via related V1a and V2 receptors (V1aR and V2R), respectively. Barusiban - [Mpa 1 -D-Trp 2 -Ile 3 -allo-Ile 4 -Asn5-Abu 6 -Mol 7 ], FE200 440 - a potent and selective OT antagonist, appears promising in preventing from premature birth. In this work, molecular modeling of barusiban complexes with OTR, V1aR and V2R is described. The modeling consists of: (1) ligand-receptor docking; (2) selection of two best complexes per each receptor, based on energetic and other criteria; and (3) relaxation of the latter by 1-ns molecular dynamics (MD) in the fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) lipid bilayer. The comparison of the ligand-host interactions among the three types of MD-relaxed barusiban-receptor complexes, leads to a hypothesis that it is a unique interaction involving the ligand D-Trp 2 in the barusiban-OTR system that could be responsible for the potency and selectivity of the antagonist. The hypothesis, that barusiban might be an inverse agonist of OTR is advanced. The finding is experimentally verifiable and if true, it may be helpful in devising new valuable OTR, VlaR and V2R antagonists.