Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor (original) (raw)
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Journal of Medicinal Chemistry, 2009
Homology modeling of the human A 2A adenosine receptor (AR) based on bovine rhodopsin predicted a protein structure that was very similar to the recently determined crystallographic structure. The inaccuracy of previous antagonist docking is related to the loop structure of rhodopsin being carried over to the model of the A 2A AR and was rectified when the β 2-adrenergic receptor was used as a template is used for homology modeling. Docking of the triazolotriazine antagonist ligand ZM241385 1 was greatly improved by including water molecules of the X-ray structure or by using a constraint from mutagenesis. Automatic agonists docking to both a new homology modeled receptor and the A 2A AR crystallographic structure produced similar results. Heterocyclic nitrogen atoms closely corresponded when the docked adenine moiety of agonists and 1 were overlayed. The cumulative mutagenesis data, which support the proposed mode of agonist docking, can be reexamined in light of the crystallographic structure. Thus, homology modeling of GPCRs remains a useful technique in probing the structure of the protein and predicting modes of ligand docking.
Journal of Medicinal Chemistry
To design and synthesize new potent and selective antagonists of the human A 3 adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecular model of the receptor built by homology modeling. The alignment of the ligands proposed by Catalyst was then used to manually dock a set of known A 3 antagonists into the binding site, and as a result, the model was able to explain the different binding mode of very active compounds with respect to less active ones and to reproduce, with good accuracy, free energies of binding. The docking highlighted that the nonconserved residue Tyr254 could play an important role for A 3 selectivity, suggesting that a mutagenesis study on this residue could be of interest in this respect. The reliability of the whole approach was successfully tested by rational design and synthesis of new compounds.
Journal of Medicinal Chemistry, 2005
A molecular model of the human A 2B adenosine receptor containing seven transmembrane R helices connected by three intracellular and three extracellular hydrophilic loops had been constructed. A molecular docking of seven structurally diverse xanthine antagonists of the A 2B receptor was performed, and the differences in their binding modes were investigated. The 1 ns molecular dynamics (MD) simulations of several obtained ligand-receptor complexes inserted into the phospholipid bilayer were carried out. The conformational changes of the A 2B receptor occurring during MD simulations were explored, and the stable binding modes of the studied antagonists were determined. According to the models presented in this work, the involvement of the His251, Asn282, Ser92, Thr89, and some aromatic residues in ligand recognition was determined. The obtained binding modes of the A 2B antagonists demonstrate good agreement with the site-directed mutagenesis data. Figure 2. Binding modes of the A2B receptor antagonists.
Novel approaches for modeling of the A1 adenosine receptor and its agonist binding site
Proteins: Structure, Function, and Bioinformatics, 2004
The present work describes the building of a human A 1 adenosine receptor (hA 1 AR) model, based on the X-ray crystal structure of bovine rhodopsin, and its use as a basis for the investigation of some important structural characteristics of the receptor. One of the issues investigated was the protonation position of two histidine residues known to influence ligand binding, with protonation of His251 (6.52) in epsilon position and His278 (7.43) in delta position showing the best agreement with experimental evidence. The model was also used to study the position and structural role of water molecules present in the helical bundle. Finally, the binding site location and the ligand docking were investigated using an objective strategy. A suitable site for the binding of the ribose moiety of adenosine was first postulated and further confirmed by means of a novel chemometric strategy based on GRIND descriptors. Using this position as an anchor point, the binding of adenosine was studied by docking and molecular dynamics simulations obtaining two putative binding positions in good agreement with experimental data. Proteins 2004; 54:705-715.
In Silico Pharmacology, 2013
Purpose: A 2B receptor agonists are studied as possible therapeutic tools for a variety of pathological conditions. Unfortunately, medicinal chemistry efforts have led to the development of a limited number of potent agonists of this receptor, in most cases with a low or no selectivity versus the other adenosine receptor subtypes. Among the developed molecules, two structural families of compounds have been identified based on nucleoside and non-nucleoside (pyridine) scaffolds. The aim of this work is to analyse the binding mode of these molecules at 3D models of the human A 2B receptor to identify possible common interaction features and the key receptor residues involved in ligand interaction.
Journal of Medicinal Chemistry, 2002
We present a combined computational study aimed at identifying the three-dimensional structural properties required for different classes of compounds to show antagonistic activity toward the A 1 adenosine receptor (AR). Particularly, an approach combining pharmacophore mapping, molecular alignment, and pseudoreceptor generation was applied to derive a hypothesis of the interaction pathway between a set of A 1 AR antagonists taken from the literature and a model of the putative A 1 receptor. The pharmacophore model consists of seven features and represents an improvement of the N 6 -C8 model, generally reported as the most probable pharmacophore model for A 1 AR agonists and antagonists. It was used to build up a pseudoreceptor model able to rationalize the relationships between structural properties and biological data of, and external to, the training set. In fact, to further assess its statistical significance and predictive power, the pseudoreceptor was employed to predict the free energy of binding associated with compounds constituting a test set. While part of these molecules was also taken from the literature, the remaining compounds were designed and synthesized by our research group. All of the new compounds were tested for their affinity toward A 1 , A 2a , and A 3 AR, showing interesting antagonistic activity and A 1 selectivity.
Molecular modeling of the human A2a adenosine receptor
Doklady. Biochemistry and biophysics
To date, four subtypes of adenosine receptors (A1, A2a, A2b, and A3) are known. All of them are contained in different types of mammalian and human tissues and play a key role in some biological processes. It was shown that the activation of the A1 and A3 receptors leads to a decrease in the cAMP level, whereas the activation of the A2a and A2b subtypes increases it . In addition, stimulation of the A2a receptors results in the inhibition of the functional activity of the D2 dopamine receptors, which is of great importance for the development of mental and neurological diseases . Similar to other G protein-coupled receptors, adenosine receptors contain a typical transmembrane domain formed by seven α helices (TM1-TM7) linked pairwise with three extracellular and three intracellular hydrophilic loops of various lengths. It is known that the binding site for the agonists and antagonists of these receptors is located in the transmembrane domain. Numerous ligands of the adenosine receptors (both agonists and antagonists) differing in selectivity and effectiveness have been found . The experiments on mutagenesis of the binding sites for adenosine receptors allowed determination of the amino acids that are predominantly involved in the ligand binding [4-6]. However, the molecular structure of these receptors and the mechanisms of ligand-receptor interactions remain poorly understood. This is mainly due to the absence of X-ray data on the transmembrane domains of not only adenosine receptors, but also other G-protein-coupled receptors. In view of this, the computer molecular simulation remains the main tool for studying the structure of these receptors and determining the mechanism of ligand binding. Earlier, we constructed models of the human adenosine receptors A1 [7] and A2b .
Journal of Medicinal Chemistry, 2021
Distinguishing compounds' agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (K i = 2.40 nM) as a potent human A 3 adenosine receptor (hA 3 AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA 3 AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and threedimensional (3D) structural network analysis of the receptor− ligand complex, the results indicated that the hydrogen bonding with Thr94 3.36 and His272 7.43 could make a stable interaction between the 3'-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds' actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.
A binding kinetics study of human adenosine A3 receptor agonists
Biochemical Pharmacology, 2018
While equilibrium binding affinities and in vitro functional antagonism of CB1 receptor antagonists have been studied in detail, little is known on the kinetics of their receptor interaction. In this study, we therefore conducted kinetic assays for nine 1-(4,5-diarylthiophene-2-carbonyl)-4-phenylpiperidine-4carboxamide derivatives and included the CB1 antagonist rimonabant as a comparison. For this we newly developed a dual-point competition association assay with [ 3 H]CP55940 as the radioligand. This assay yielded Kinetic Rate Index (KRI) values from which structure-kinetics relationships (SKRs) of hCB1 receptor antagonists could be established. The fast dissociating antagonist 6 had a similar receptor residence time (RT) as rimonabant, i.e. 19 and 14 min, respectively, while the slowest dissociating antagonist (9) had a very long RT of 2222 min, i.e. pseudo-irreversible dissociation kinetics. In functional assays, 9 displayed insurmountable antagonism, while the effects of the shortest RT antagonist 6 and rimonabant were surmountable. Taken together, this study shows that hCB1 receptor antagonists can have very divergent RTs, which are not correlated to their equilibrium affinities. Furthermore, their RTs appear to define their mode of functional antagonism, i.e. surmountable vs. insurmountable. Finally, based on the recently resolved hCB1 receptor crystal structure, we propose that the differences in RT can be explained by a different binding mode of antagonist 9 from short RT antagonists that is able to displace unfavorable water molecules. Taken together, these findings are of importance for future design and evaluation of potent and safe hCB1 receptor antagonists. d N.A. not applicable.