Abstract (EN):
A2B adenosine receptor (A2BAR) antagonists have been proposed as an attractive pharmacological tool for the treatment of
several diseases, such as asthma, Alzheimer’s disease, cystic fibrosis and type II diabetes [1]. A wide variety of A2BAR
antagonists can currently be found in the literature, specifically xanthine derivatives [2]; however, other chemicals, such as
chromone structures, are little studied, and they could be new A2BAR ligands.
In this work, our attention has been pointed out toward the evolution of the new quantitative structure–activity
relationships (QSAR) model based on chromone structures to predict affinity for A2B ARs and using molecular descriptors
derived from TOPS-MODE approach (http://www.modeslab.com). With the compilation of a dataset of chromones
synthesized in our laboratories, or elsewhere, and testing their ability to displace [3H]-DPCPX from cloned human A2B
adenosine, we recognized a unique opportunity to attempt to build a predictive QSAR model. The regression QSAR model
is given below together with the regression statistical parameters:
%I ¼ 10:71 þ 7:88 107 m0mDip
11
1:05 102 m0mDip2
5
þ 0:203m1m
AbPBH2
4
N ¼ 20 s ¼ 8:14 R2 ¼ 92:20 F ¼ 32:80 q2
LOO
¼ 89:17 p < 105
ThisQSAR model allowed us to carry out a fragment analysis of the set ofA2BAR antagonist to find the best structural features
that allow the development of new potent antagonist. Substructural analysis also helped to understand the influence of the
physicochemical properties on modulation of binding affinity at A2BAR subtype. This is the first study where a substructural
analysis of A2BAR supports the design and selection of novel candidates structurally based on chromone scaffold.
Language:
Portuguese
Type (Professor's evaluation):
Scientific
Contact:
qomaca@uvigo.es