Molecular modeling of adenosine receptors: new results and trends

Abstract

Adenosine is a ubiquitous neuromodulator, which carries out its biological task by stimulating four cell surface receptors (A(1), A(2A), A(2B), and A(3)). Adenosine receptors (ARs) are members of the superfamily of G protein-coupled receptors (GPCRs). Their discovery opened up new avenues for potential drug treatment of a variety of conditions such as asthma, neurodegenerative disorders, chronic inflammatory diseases, and many other physiopathological states that are believed to be associated with changes in adenosine levels. Knowledge of the 3D structure of ARs could be of great help in the task of understanding their function and in the rational design of specific ligands. However, since GPCRs are membrane-bound proteins, high-resolution structural characterization is still an extremely difficult task. For this reason, great importance has been placed on molecular modeling studies and, particularly in the last few years, on homology modeling (HM) techniques. The publication of the first high-resolution crystal structure for bovine rhodopsin (bRh), a GPCR superfamily member, provides the option of utilizing HM to generate 3D models based on detailed structural information. In this review we report, analyze, and compare the main experimental data, computational HM procedures and validation methods used for ARs, describing in detail the most successful results.

Molecular modeling of A1 and A2A adenosine receptors: Comparison of rhodopsin‐ and β2‐adrenergic‐based homology models through the docking studies

“…During current investigation, no one of our automated docking attempts of DPCPX produced the same results due to the H-bonds network of this ligand, as in the previous models discussed in ref. 60. Nevertheless, the lipophilic interactions of DPCPX presented here for the Rho-based A 1 AR are in consistence with most of the A 1 AR modeled previously.…”

“…60. The most widely discussed antagonist for A 1 AR is DPCPX, however, its docking was performed manually followed by MD simulations.…”

Ligand Binding and Subtype Selectivity of the Human A2A Adenosine Receptor

“…The recently solved human A 2A AR-ZM241385 co-crystal structure revealed that the prototypical non-xanthine antagonist, ZM241385, binds very differently to the receptor than had been predicted by models based on rhodopsin binding to retinal (7,8). The long axis of ZM241385 lies orthogonal to the membrane plane and has a large number of interactions with residues in TM domains 5-7, and extracellular loops 2 and 3 (3).…”

“…Surprisingly, we found that the binding mode of ZM241385 to its receptor is very different from the binding of ligand to other GPCRs with known crystal structures, the beta-blockers timolol, carazolol, and cyanopindolol co-crystallized with turkey ␤ 1 -adrenoreceptor or human ␤ 2 -adrenoceptors and retinal cocrystallized with bovine and squid rhodopsin, and binding of these ligands to their cognate receptors has very little overlap with ZM241385 binding to A 2A AR when all available receptor structures are superimposed (6). In addition, the orientation of ZM241385 in the binding pocket deviates greatly from that of homology models, which used the rhodopsin structure as a template (7)(8). Therefore, models for ligand-A 2A AR interac-tions based upon these other GPCR-ligand structures can give only rough picture of ligand binding (9).…”

The Structure of the Adenosine Receptors

“…3A). This cannot be reconciled with earlier molecular modeling studies based on rhodopsin homology models in which ZM241385 and other antagonists were docked into a binding site emulating that of the b 2 -adrenoceptor and rhodopsin (Martinelli & Tuccinardi, 2008;Yuzlenko & Kiec-Kononowicz, 2009). Second, the organization of the extracellular loops is markedly different from those of the b 1 -adrenoceptor, the b 2 -adrenoceptor, or the bovine and squid rhodopsins.…”