Binding of k-OR selective morphine opioids

Binding of k-OR selective morphine opioids

Morphine is one of the most physiologically relevant opioid molecules known and its use as a treatment of acute and chronic pain is well established. It also serves as a precursor for other opioid molecules in the pharmaceutical industry. Various binding models and mutagenesis studies suggested mechanisms of action of this potent alkaloid but the elucidation of the crystal structure of k-OR provided ultimate evidence on its structure-function relationship. The same authors that published the crystal structure of the JDTic/k-OR complex also characterized, in the same publication, the binding mechanism of morphine analogues nor-BNI and GNTI (Figure 8), with the aim to clarify the interaction events which bring about the physiological changes caused by morphine and laying out the ground work for the development of synthetic analogues, which exploit these characterized interactions to improve binding selectivity, reduce side-effects or provide a tighter control over opioid receptor activity.

                The crystal structure of nor-BNI/k-OR and GNTI/k-OR showed a number of shared and unique interactions in the ligand binding pocket of the k-OR. They both formed the canonical salt bridge with Asp138 and a hydrogen bond with Tyr139 (both of these interactions are conserved in morphine-binding sites). Both morphine-analogues contain a basic moiety, which form a salt-bridge with Glu297 (located on the entrance of the ligand binding pocket). Both of these molecules also displayed the same hydrophobic interactions at the kOR-specific Ile294 residue as well as a highly complementary Van der Waals interface through their naltrexone moiety. A number of different molecular interactions were also seen between the different morphine analogues and the residues in the pocket. For example, nor-BNI displayed polar interactions with Glu209 and Ser211 in the ECL2 whilst GNTI didn’t.

                An interesting common interaction motif between JDTic and these morphine analogues was discovered where the cyclopropyl moiety of both nor-BNI and GNTI posses the same position as the isopropyl moiety of JDTic, making hydrophobic contact with conserved residue Trp287. These studies strongly suggested that although morphine analogues shared some common interaction features with those occurring in the elucidated JDTic/k-OR complex, like hydrophobic contacts with His291 in the aromatic cluster or polar contacts with Asp138, the interactions of these analogues with the k-OR pockets differed to an extent that suggested a high degree of selectivity was conserved even between significantly different ligands and thus illustrated the facilitated recognition multivalency of the k-OR through the residues lining the ligand-binding pocket. The most representative example is the importance of the Glu297 residue for the anchoring of nor-BNI and GNTI and its low significance in maintaining the 1000-fold selectivity of JDTic binding to kOR. Another example is the coinciding behaviour of the morphine analogues with the Schwyzer's message-address model for peptide recognition elements and the apparent inapplicability of this concept to JDTic interaction with k-OR. Most of the characterized interactions between the morphine analogues and the receptors coincided with or were confirmed by mutagenesis experiments.

                  Figure 8. Structures of morphine analogues. A) nor-BNI. B) GNTI. Note how such significant structures (also compare with that of JDTic) share binding interactions with the ligand binding pocket of the kappa opioid receptor and are yet highly selective in their binding^[4][5].