Pharmacophore Pattern Identification of Tachykinin Receptor Selective Peptide Agonists: Implications in Receptor Selectivity

Abstract

Abstract:The mammalian tachykinin (TK) peptides and their three Neurokinin (NK1, NK2 and NK3) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests the pathophysiological role of TKs in various diseases including asthma, emesis and depression. The TK-NK receptor interactions and overlapping functions mediated by each NK receptor indicate added therapeutic benefit of using multiple NK receptor blockade. In the absence of structural data on neurokinin receptors, the membrane-induced structure of tachykinins play an important role as a first step towards understanding structure-activity relationship. A comparison of the conformational features of different NK1, NK2 and NK3 receptor agonists highlights several features which might be responsible for determining selectivity for the particular receptor subtype. An attempt has been made to correlate the observed conformational differences to the binding ability and biological activity of various NK1, NK2 and NK3 receptor agonists. The membrane bound conformations of tachykinins have been used as a starting point, leading to useful pharmacophore patterns that can be used for identifying lead structures with novel scaffolds.

Molecular Modeling of the Peptide Agonist-Binding Site in a Neurokinin-2 Receptor

“…The docking data further correlate well with the pharmacophore pattern proposed by us for NK-2 agonists, 40 and a pharmacophore pattern complementarity has been observed in the ligand-receptor complex, wherein the aromatic side chain of Phe 6 is found to closely interact with an aromatic microdomain in the NK-2 receptor, and hydrophobic Leu 9 and Met 10 are found to interact with hydrophobic residues of the receptor (Figure 1). This is further in accordance with the hypothesis that the binding site will be complementary to the distribution of polar/nonpolar atoms of the ligands in their bioactive conformations.…”

Molecular Modeling of Neurokinin B and Tachykinin NK3 Receptor Complex

“…The docking data, further, correlate well with the pharmacophore pattern proposed by us for NK 3 agonists, and a pharmacophore pattern complementarity is observed in the ligand–receptor complex (Figure ). This is further in accordance with the hypothesis that the binding site will be complementary to the distribution of polar/nonpolar atoms of the ligands in their bioactive conformations.…”

“…The key peptide residues F6, L9, and M10, identified as being important for pharmacological function as well as being identified in our study as pharmacophore points, 66 were found to have significant interactions with the NK 3 receptor. The pharmacophore pattern complementarity is observed for the NK 3 /NKB complex with the three hydrophobic pharmacophores of NKB being bound to three predominantly hydrophobic pockets of the receptor.…”