title: Linear and nonlinear 3D-QSAR approaches in tandem with ligand-based homology modeling as a computational strategy to depict the pyrazolo-triazolo-pyrimidine antagonists binding site of the human adenosine A2A receptor.
abstract: The integration of ligand- and structure-based strategies might sensitively increase the success of drug discovery process. We have recently described the application of Molecular Electrostatic Potential autocorrelated vectors (autoMEPs) in generating both linear (Partial Least-Square, PLS) and nonlinear (Response Surface Analysis, RSA) 3D-QSAR models to quantitatively predict the binding affinity of human adenosine A3 receptor antagonists. Moreover, we have also reported a novel GPCR modeling approach, called Ligand-Based Homology Modeling (LBHM), as a tool to simulate the conformational changes of the receptor induced by ligand binding. In the present study, the application of both linear and nonlinear 3D-QSAR methods and LBHM computational techniques has been used to depict the hypothetical antagonist binding site of the human adenosine A2A receptor. In particular, a collection of 127 known human A2A antagonists has been utilized to derive two 3D-QSAR models (autoMEPs/PLS&RSA). In parallel, using a rhodopsin-driven homology modeling approach, we have built a model of the human adenosine A2A receptor. Finally, 3D-QSAR and LBHM strategies have been utilized to predict the binding affinity of five new human A2A pyrazolo-triazolo-pyrimidine antagonists finding a good agreement between the theoretical and the experimental predictions.
authors.affiliation: Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, I-35131 Padova, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Michielan
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bacilieri
authors.forename: Andrea
authors.initials: A
authors.lastname: Schiesaro
authors.forename: Chiara
authors.initials: C
authors.lastname: Bolcato
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pastorin
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Karl Norbet
authors.initials: KN
authors.lastname: Klotz
authors.forename: Chosei
authors.initials: C
authors.lastname: Kaseda
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011720:Pyrazoles; D011743:Pyrimidines; D021281:Quantitative Structure-Activity Relationship; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014230:Triazoles
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles