Adenosine receptors (ARs) are G-protein-coupled receptors (GPCRs) that mediate the important extracellular role of adenosine. Four AR subtypes exist, all of them of is significant pharmacological interest due to their involvement in several inflammatory processes (A2A and A3); respiratory pathological events such as allergic asthma (A2B and A3); vascular diseases (A2A), arrhythmias and stroke (A1). Most AR antagonists are based on complex heterocycles to accomplish with receptor specificity. This has the drawback of poor pharmacokinetic properties. In my research group, we combine homology modeling, molecular dynamics (MD), docking, 3D-QSAR and free energy calculations, to assist on the discovery, characterization and design of new chemical entities as antagonists of each of the adenosine receptors [1]. Starting from the crystal structures of the A2AAR, we have generated 3D structures of all AR members, with family-curated alignments, homology modeling and molecular-dynamics (MD), as implemented in GPCR-ModSim (http://gpcr-modsim.orf) Thereafter, docking screens combined with detailed description of ligand-receptor interactions, including 3D-QSAR or MD analysis, allow the identification of potent and selective A3 [2] and A2B [3] antagonists. In the process, molecular determinants of selectivity were identified and subsequently exploited in further ligand designs [4]. Finally, our recently developed free energy perturbation schemes now allow the evaluation of the effect of single point mutations on ligand binding, a unique advantage of our computational pipeline [5]. 1 Gutiérrez-de-Terán et al, Meth Mol Biol, 2015, 1272:271 2 Yaziji et al, J Med Chem, 2011, 54:457 3 Crespo et al, ACS Med Chem Lett, 2013, 4:1031 4 Yaziji et al, Eur J Med Chem, 2013, 59:235 5 Keränen et al, Chemm Commun, 2015, 51:3522; Keränen et al, Plos Comp Biol, 2014, 9:e108492

Combining ligand-based and structure-based ligand design towards the development of potent and selective antagonists for the adenosine receptors

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.