Quantitative Structure Activity Relationship and Pharmacophore Studies of Adenosine Receptor A_2B Inhibitors

Abstract

Adenosine receptor A2B (ADoR A2B) is an important G protein-coupled receptor (GPCR) of the rhodopsin family, and plays a pivotal role in gastrointestinal, neurological and hypersensitive disorders. QSAR and pharmacophore studies were carried out using 63 ADoR A2B inhibitor molecules to characterize molecular features and structural requirements for biological interaction. QSAR modelling using genetic algorithm- partial least squares (G/PLS) method identified molecular shape, size electrophilicity and conformational flexibility as important descriptors for these compounds affinity to the receptor. Further analysis of pharmacophore model revealed hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), hydrophobic aliphatic (HY-ala) and hydrophobic aromatic (HY-aro) as the crucial molecular features that predict binding affinity of these compounds to ADoR A2B. These observations provide important insights to the rationale development of novel and potent compounds against ADoR A2B.

Insights into binding modes of adenosine A2B antagonists with ligand-based and receptor-based methods

“…Hypo1 was not only fitted well with the test set containing 109 A 2B antagonists and enrichments test, but also was in agreement with the A 2B homology model. There were two similar work reported by Wei et al [31] and Joseph et al [32], recently. Compared with those two models, our model was better than them in two aspects: compounds in the training set had more diversity, and our R tr-set , R test-set and other cost criteria were much improved.…”

“…Ten optimal pharmacophore hypotheses were generated for each running, which were automatically ranked according to their corresponding "total cost" values, defined as the sum of error cost, weight cost, and configuration cost. Four pharmacophore features: HBA, HBD, RA and HYD-AL were selected from the feature dictionary of CATALYST according to literature reports [31,32]. In order to consider the PI feature, four additional trials were performed (Table 2), in which protonational state of each molecule was made in CATALYST (see Supplementary Fig.…”

“…Unfortunately, the crystal structure of most GPCR receptors was not resolved, including A 2B receptor. In the aspect of ligand-based method, 3D-QSAR (CoMFA) [25] and pharmacophore modeling methods [31,32] had been used to predict binding affinity of A 2B antagonists. But these results were not so satisfactory.…”

“…But these results were not so satisfactory. Wei et al [31] created a pharmacophore model based on only five A 2B antagonists with CATALYST HipHop method, whereas Joseph et al [32] built the pharmacophore model based on 23 A 2B agonists derived from the same skeleton with CATALYST HypoGen method. Comparing these two models, it is easy to see that their training set had no diversity and their pharmacophore models only based on (continued on next page) [35].…”

Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3‐d]pyrimidine derivatives

“…The A 2A receptor antagonists may be useful for the treatment of neurodegenerative movement disorders such as Parkinson's and Huntington's disease, and dystonias such as restless leg syndrome, dyskinesias such as those caused by prolonged use of neuroleptic and dopaminergic drugs . A 2B receptor antagonists are found to be useful for the treatment of type 2 diabetes and asthma . CVT‐6883, a potent and selective A 2B receptor antagonist, was found to be efficacious in various animal models of asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis and reported as the first A 2B ‐specific antagonists entered in clinical trials …”