A3 Adenosine Receptor: homology modeling and3D-QSAR studies

Adenosine receptors (AR) belong to the superfamily of G-protein-coupledreceptors (GPCRs). They are divided into four subtypes (A1, A2A, A2B, and A3)[1], and can be distinguished on the basis of their distinct molecular structures,distinct tissues distribution, and selectivity for adenosine analogs [2,3]. The hA3R,the most recently identified adenosine receptor, is involved in a variety ofintracellular signaling pathways and physiological functions [4]. Expression ofA3R was reported to be elevated in cancerous tissues [5], and A3 antagonists havebeen proposed for therapeutic treatments ofcancer. The recent literature availability ofcrystal structure of hA2A adenosine receptor(PDB code: 3EML) provided us a newtemplate for A3R homology modeling. Thevalidation of the obtained structure model wasperformed by inspecting the Ramachandranplot (Fig. 1). The modeled protein wasoptimized using nanosecond scale moleculardynamics simulation. One hundred twenty twoactive and selective compounds were docked into the obtained model usingInduced Fit Docking [6] and used as training set to generate pharmacophore modelsby means PHASE [7]. Energy-optimized pharmacophore mapping was performed;to each pharmacophore feature site was assigned an energetic value as the sum ofthe GLIDE XP contributions of the atoms included in the site. This pharmacophoremodel addresses the prevalent features to be used for the search of new inhibitors.Therefore it was employed as template to screen the ZINC database in the attemptto find new potent and selective human A3R antagonists.[1] B.B. Fredholm, A.P. Ijzerman, K.A. Jacobson, K.N. Klotz, J. Linden, Pharmacol. Rev., 53,2001, 527.[2] P.G. Baraldi, R. Romagnoli, D. Preti, F. Fruttarolo, M.D. Carrion, M.A. Tabrizi, Curr. Med.Chem., 13, 2006, 3467.[3] M.D.Okusa, Am. J. Physiol. Renal Physiol., 282, 2002, F10.[4] A.Ochaion, S. Bar Yehuda, S. Cohen, F. Barer, R. Patoka, L. Del-Valle, G. Perez-Liz, J. Ophir,R. Galili-Mosberg, T. Reitblat, H. Amital, P. Fishman, Ann. Rheum. Dis., 66, 2007, 446.[5] L.Madi, A. Ochaion, L. Rath-Wolfson, S. Bar-Yehuda, A. Erlanger, G. Ohana, A. Harish, O.Merimski, F. Barer, P. Fishman, Clin. Cancer Res., 10, 2004, 4472.[6] Schrödinger Suite 2009 Induced Fit Docking protocol; Glide version 5.5, Schrödinger, LLC,New York, NY, 2009; Prime version 2.1, Schrödinger, LLC, New York, NY, 2009.[7] Phase, version 3.1, Schrödinger, LLC, New York, NY, 2009.