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 A^sub 2A^ Receptor

• Published in: Journal of chemical information and modeling Vol. 48; no. 2; p. 350
• Main Authors: Michielan, Lisa, Bacilieri, Magdalena, Schiesaro, Andrea, Bolcato, Chiara, Pastorin, Giorgia, Spalluto, Giampiero, Cacciari, Barbara, Klotz, Karl Norbet, Kaseda, Chosei, Moro, Stefano
• Format: Journal Article
• Language: English
• Published: Washington American Chemical Society 01.02.2008
• Subjects: Adenosine; Binding sites; Biochemistry; Molecules; Studies
• ISSN: 1549-9596; 1549-960X

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 A... 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 A... receptor. In particular, a collection of 127 known human A... antagonists has been utilized to derive two 3D-QSAR models (autoMEPsi PLS&RSA). In parallel, using a rhodopsin-driven homology modeling approach, we have built a model of the human adenosine A... receptor. Finally, 3D-QSAR and LBHM strategies have been utilized to predict the binding affinity of five new human A... pyrazolo-triazolo-pyrimidine antagonists finding a good agreement between the theoretical and the experimental predictions. (ProQuest: ... denotes formulae/symbols omitted.)