Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations

Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5'-GNTI is an antagonist while 6'-GNTI is an agonist of the kappaOR opioid receptor. To explore how a subtle alteration of the ligand structure influences the receptor activity, we investigated two concurrent processes: the final steps of ligand binding at the receptor binding site and the initial steps of receptor activation. To trace these early activation steps, the membranous part of the receptor was built on an inactive receptor template while the extracellular loops were built using the ab initio CABS method. We used the simulated annealing procedure for ligand docking and all-atom molecular dynamics simulations to determine the immediate changes in the structure of the ligand-receptor complex. The binding of an agonist, in contrast to an antagonist, induced the breakage of the "3-7 lock" between helices TM3 and TM7. We also observed an action of the extended rotamer toggle switch which suggests that those two switches are interdependent.