Homology modeling, molecular dynamics and docking simulations of rat A2A receptor: a three-dimensional model validation under QSAR studies
Date
2013-12-17
Authors
Soriano-Ursua, Marvin A
Deeb, Omar
Segura-Cabrera, Aldo
Correa-Basurto, Jose
Journal Title
Journal ISSN
Volume Title
Publisher
Bentham Science Publishers
Abstract
Understanding the three-dimensional structure
(3-D) of GPCRs (G protein coupled receptors) can
aid in the design of applicable compounds for the
treatment of several human disorders. To this end,
several 3-D models have been obtained in recent
years. In this work, we have built the rat
adenosine receptor model (rA2AR) by employing
computational tools. First, the 3-D rA2AR model
was built by homology modeling using the human
adenosine receptor (hA2AR) structure (PDB codes:
3EML) as a template. Then, the rA2AR model was
refined by molecular dynamics simulations, in
which the initial and refined 3-D structures were
used for molecular docking simulations and
Quantitative structure-activity relationship (QSAR)
studies using a set of known experimentally tested
ligands to validate this rA2AR model. The results
showed that the hindrance effect caused by ribose
attached to agonists play an important role in
activating the receptor via formation of several
hydrogen bonds. In contrast, the lack of this
moiety allows blocking of the receptor. The
theoretical affinity estimation shows good
correlation with reported experimental data.
Therefore, this work represents a good example
for getting reliable GPCR models under
computational procedures.
Description
Keywords
A2A adenosine receptor , homology modeling , xanthine , drug development , rat brain , Parkinson’s disease