1 research outputs found
Discovery of Novel Adenosine Receptor Antagonists through a Combined Structure- and Ligand-Based Approach Followed by Molecular Dynamics Investigation of Ligand Binding Mode
An intense effort is made by pharmaceutical
and academic research
laboratories to identify and develop selective antagonists for each
adenosine receptor (AR) subtype as potential clinical candidates for
“soft” treatment of various diseases. Crystal structures
of subtypes A<sub>2A</sub> and A<sub>1</sub>ARs offer exciting opportunities
for structure-based drug design. In the first part of the present
work, Maybridge HitFinder library of 14400 compounds was utilized
to apply a combination of structure-based against the crystal structure
of A<sub>2A</sub>AR and ligand-based methodologies. The docking poses
were rescored by CHARMM energy minimization and calculation of the
desolvation energy using Poisson–Boltzmann equation electrostatics.
Out of the eight selected and tested compounds, five were found positive
hits (63% success). Although the project was initially focused on
targeting A<sub>2A</sub>AR, the identified antagonists exhibited low
micromolar or micromolar affinity against A<sub>2A</sub>/A<sub>3</sub>, ARs, or A<sub>3</sub>AR, respectively. Based on these results,
19 compounds characterized by novel chemotypes were purchased and
tested. Sixteen of them were identified as AR antagonists with affinity
toward combinations of the AR family isoforms (A<sub>2A</sub>/A<sub>3</sub>, A<sub>1</sub>/A<sub>3</sub>, A<sub>1</sub>/A<sub>2A</sub>/A<sub>3</sub>, and A<sub>3</sub>). The second part of this work
involves the performance of hundreds of molecular dynamics (MD) simulations
of complexes between the ARs and a total of 27 ligands to resolve
the binding interactions of the active compounds, which were not achieved
by docking calculations alone. This computational work allowed the
prediction of stable and unstable complexes which agree with the experimental
results of potent and inactive compounds, respectively. Of particular
interest is that the 2-amino-thiophene-3-carboxamides, 3-acylamino-5-aryl-thiophene-2-carboxamides,
and carbonyloxycarboximidamide derivatives were found to be selective
and possess a micromolar to low micromolar affinity for the A<sub>3</sub> receptor