Structural comparison of mu-opioid receptor selective peptides confirmed four parameters of bioactivity.
Structural determinants of binding to the mu-opioid receptor, an important target in analgesia, attract great scientific attention. Many natural and synthetic peptides and peptidomimetics were shown previously to bind to this receptor selectively but there is no consensus about the structure responsible for biological activity. No high resolution structure of this receptor is available and the binding site of ligands is not exactly known. However, mu-opioid ligands with similar affinity and selectivity should possess at least one common structural feature. Comparative structural analysis of such ligands, considering adequate representation of binding conditions, may reveal key features of bioactivity. In this study ten mu-opioid receptor ligands, DAMGO, Tyr-W-MIF-1, morphiceptin, endomorphin-1 and 2 and their analogues, possessing different affinity and selectivity, were examined using molecular dynamics. Conformational preference of these molecules was determined in H(2)O and DMSO along with structural properties previously proposed to be important for binding. Four of such structural requirements were confirmed to be important, providing a possible structural model of receptor binding. Simultaneous fulfillment of these requirements results most likely in high affinity binding to the mu-opioid receptor.
Borics
Attila
A
Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, 62 Temesvári körút, Szeged H-6720, Hungary. aborics@brc.hu
Tóth
Géza
G
D000595:Amino Acid Sequence; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D010455:Peptides; D017450:Receptors, Opioid, mu