A molecular model for an anionic opiate mu-receptor: affinity and activation of morphine conformers

In this study, the minimal neglect of differential overlap, hydrogen bonding corrected (MNDO/H) method was used to construct an explicit three component mu-opioid receptor binding site composed of formate (Glu-, Asp-), H2O (Ser, Thr) and NH4+ (Lys+, Arg+) which has optimum interactions with the protonated amine and polar oxygen regions of morphine, respectively. These moieties are common to most classes of opioids and are thought to be involved in key interactions of the protonated form with the receptor leading to recognition and activation. Two predominant conformers of morphineH+, N-Me (equatorial) and N-Me (axial) were used as templates for construction of the binding site. In these studies, a plausible recognition mechanism involving electrostatic interaction between the protonated amine and an anionic receptor site, together with a proton-donating phenolic group and proton-accepting polar oxygens was characterized. The role of hydration of both the receptor site and morphine in determining affinity was also explicitly considered. The results strongly indicate that the high-affinity binding of morphineH+ to an 'anionic' receptor site is due mainly to a large entropy term resulting from expulsion of H2O from the receptor site upon introduction of morphine. A possible mechanism of receptor activation was also explored involving proton transfer from morphine to the receptor. Two results obtained support the plausibility of this mechanism: the barrier to proton transfer is reduced by receptor interaction with the polar oxygens and a conformational change occurs in the model receptor during this process.