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Document A. Receptor Targets Figure 20 Iterative cycle(s) for structure-based drug design Page 592 Amongst the known superfamilies of cell membrane anchored receptors, significant research has been focused on GPCR targets (Table 1). The GPCR superfamily of receptors consist of seven transmembrane-spanning (TM) helices. Sequence homology among them varies from 25–70% (for reviews see References 33, 122–132). The initial development of 3D structural models of GPCR targets has been developed from homology-building methodologies based on a low-resolution structure of bacteriorhodopsin [133]. Representative examples of recent studies that provide insight to pharmacophore modeling and structure-based drug design of peptide, peptidomimetic, and nonpeptide ligands are discussed below. 3 G-Protein-Coupled Receptors Recent studies have explored several GPCR targets with respect to ligand-receptor binding interactions using site-directed mutagenesis to explore agonist http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_592.html (1 of 2) [4/9/2004 1:18:59 AM]
Document Page 593 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_593.html [4/9/2004 1:19:20 AM]
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Page 765 and 766: Document Acknowledgments Page 620 I
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