In the course of this fiscal year, we have worked on the GPCR systems described in the following paragraphs. Some of these systems are very well characterized in the literature, where a wealth of information, including experimentally derived structures, can be found. Thus, they constitute an ideal platform for the development of computational methodologies subsequently applicable to the whole superfamily. Conversely, other systems are less well characterized, but constitute attractive targets for the development of pharmaceutical agents. Beta-adrenergic receptors. The beta-adrenergic receptors (beta-ARs) reside predominantly in smooth muscles and play crucial roles in the physiology of heart and airways. Antagonists of the beta-ARs are widely used for various indications, particularly the treatment of hypertension and cardiac arrhythmias. Agonists of the beta2-AR are clinically used in the treatment of asthma. Adenosine receptors. The adenosine receptors are widely expressed in several organs of the human body, and mediate important physiological functions in the heart, lungs, blood vessels, and platelets. Muscarinic receptors. The muscarinic receptors are a family of GPCRs stimulated by acetylcholine. Ligands of the muscarinic receptors are amply used for the treatment of a variety of conditions, including Parkinsons disease. P2Y receptors. P2Y receptors are GPCRs activated by extracellular nucleotides. Of note, antagonists of the P2Y12 receptor are amply used as antithrombotic agents. In particular, during this fiscal year, we have conducted the research and accomplished the results described in the following paragraphs. 1) Finalized and published a controlled a posteriori virtual screening for beta2-adrenergic receptors ligands. Notably, we devised a way of steering the screening towards the identification of agonists or blockers. 2) Finalized and published a strategy intended to computationally classify ligands of the adrenergic receptors into agonists and blockers. Notably, the study furnished also an insightful view into the mechanism of agonist binding. 3) Studied the implications of the use of inactive and activated structures of the beta2 adrenergic receptor on the in silico screening for agonists or blockers. 4) Identified the inhibitory effect of the activation of the P2Y1 receptor on the proliferation of prostate cancer cells. Experimental collaborator: Kenneth A. Jacobson (NIDDK). 5) Identified novel ligands of the P2Y4 receptor. Experimental collaborator: Kenneth A. Jacobson (NIDDK). 6) Reviewed the involvement of purinergic receptors on platelet aggregation. Collaborator: Kenneth A. Jacobson (NIDDK). 7) Studied the structural bases underlying the formation of dimers and/or oligomers of the muscarinic M3 receptor. Experimental collaborator: Jrgen Wess (NIDDK). 8) Worked on a review of the most effective techniques for the construction and validation of homology models of G protein-coupled receptors. 9) Worked on a review on the combined use of ligand-based and docking-based techniques for the prediction of biological activities. 10) Continued a bioinformatics study, in collaboration with Carson C. Chow (NIDDK), intended to shed light onto the evolution of the GPCR superfamily.
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