Paper Citing NAMD - Abstract
Pedretti, Alessandro; Vistoli, Giulio
Modeling of human ghrelin receptor (hGHS-R1a) in its close state and validation by molecular docking
BIOORGANIC & MEDICINAL CHEMISTRY, 15:3054-3064, APR 15 2007
The objective of this study was to generate a reliable model of human ghrelin receptor (hGHS-R1a) in its close state by means of a hybrid fragmental approach in which the transmembrane bundle was modeled using the rhodopsin as the template to assure a marked closeness among the transmembrane helices, while the remaining segments (i.e., loops plus terminal domains) were modeled searching different templates to favor the local homologies. The reliability of this model was assessed docking both a tetrapeptide, which represents the ghrelin's active core, and a set of 50 peptidomimetic secretagogues taken from the literature. The analysis of obtained complexes unveils a set of stabilizing interactions with crucial hGHS-R1a residues in remarkable agreement with both mutational analyses and pharmacophore hypotheses. Also the significant correlation between docking scores and biological activities affords an encouraging validation for such hGHS-R1a model, suggesting that also the receptor in its close state (similarly to the hGHS-R1a in its open state which was modeled in our previous study, Pedretti A, Villa M, Pallavicini M, Valoti E, Vistoli G. J Med. Chem. 2006, 49, p 3077.) may be involved in ligand binding and could find fertile applications in ligand design. (c) 2007 Elsevier Ltd. All rights reserved.
