A3 Adenosine Receptor: homology modeling and 3D-QSAR studies

Abstract

Adenosine receptors (AR) belong to the superfamily of G-protein-coupled receptors (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 of intracellular signaling pathways and physiological functions [4]. Expression of A3R was reported to be elevated in cancerous tissues [5], and A3 antagonists have been proposed for therapeutic treatments of cancer. The recent literature availability of crystal structure of hA2A adenosine receptor (PDB code: 3EML) provided us a new template for A3R homology modeling. The validation of the obtained structure model was performed by inspecting the Ramachandran plot (Fig. 1). The modeled protein was optimized using nanosecond scale molecular dynamics simulation. One hundred twenty two active and selective compounds were docked into the obtained model using Induced Fit Docking [6] and used as training set to generate pharmacophore models by means PHASE [7]. Energy-optimized pharmacophore mapping was performed; to each pharmacophore feature site was assigned an energetic value as the sum of the GLIDE XP contributions of the atoms included in the site. This pharmacophore model 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 attempt to 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.