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versus antagonist ligands, and such work provides insight to pharmacophore modeling. Specific
examples of such work as focused on peptide, peptidomimetic, and/or nonpeptide ligands, and working
3D structural models of their GPCR targets include angiotensin II AT 1 and AT 2 subtypes [134],
neurokinin NK 1 and NK 2 subtypes [135], cholecystokinin/gastrin CCK A and CCK B subtypes [136],
opioid μ-, δ-, and κ-subtypes [137], vasopressin V 1A subtype [138], bradykinin B 2 subtype [139],
neurotensin [140] and α-melanotropin MC 1 subtype [141]. From such work it has been inferred that
different binding-site interactions may exist for peptide versus nonpeptide ligands as based on their
differential sensitivities to site-directed mutants of the native GPCR. The recent development of 3D
structural models of the neurotensin [140] and α-melanotropin MC 1 subtype [141] GPCRs provide
interesting case studies. Both examples provide the correlation of significant structure-activity databases
and experimentally determined (NMR) structures of key peptide analogs with predicted molecular
contacts at their respective target receptors. As illustrated in Figure 21, the proposed peptide agonist
binding interactions for neurotensin and α-melanotropin analogs at their human GPCR targets may be
used to further guide the molecular design and synthesis of “second-generation” peptidomimetic
derivatives.
In the first example, the neurotensin C-terminal octapeptide was subject to conformational searching
(~Arg-Pro-Tyr~ sequences from the Brookhaven Protein Databank), manual docking to the homologybuilt
neurotensin GPCR receptor model, and constrained molecular dynamics simulation to provide a 3D
structure of the ligand-receptor complex [140]. A compact structure of the peptide in its complexed
conformation was consistent with a Type-1 β-turn as previously determined by structural and structureactivity
studies. Key molecular contacts predicted from this neurotensin GPCR model include
hydrophobic interactions with the C-terminal Ile and Leu side chains, π-cation interactions with each
Arg residue side chain, and a “cluster” of aromatic-aromatic interactions with the Tyr side chain. No
electrostatic interactions were predicted, and the primary contact residues on the neurotensin GPCR
model were those comprising the third extracellular loop.
In the second example, the α-melanotropin (MC1) GPCR model was constructed [141] by homologybuilding
methods relative to both bacteriorhodopsin and rhodopsin fingerprint maps, and the MSH
superagonist peptides [Nle 4, D-Phe 7]-MSH and Ac-cyclo[Nle 4, Asp 5, D-Phe 7, Lys 10]-MSH 4–10-NH 2 were
modeled in conformations derived from previous experimental studies (i.e., a Type-II β-turn at the
common tetrapeptide sequence ~His-D-Phe-Arg-Trp~). Of the alternative binding modes that were
described for the above the two MSH peptide ligands, one predicts the possibility of a network of
aromatic-aromatic and hydrophobic interactions between the MC1 receptor and the D-Phe and Trp side
chains of the MSH ligand (Figure 21). In addition, this MC1 receptor model predicts multiple
electrostatic and π-cation interactions between
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