Induced fit and pharmacophore generation approach applied to A2A adenosine receptor antagonists

Receptors A2A have an important role in the regulation of mood and motor activity; the available evidence has provided the basis for the formulation of a theory according to which selective A2A adenosine receptor antagonists can be useful for the treatment of Parkinson’s Disease. To explore the binding properties of some adenosine-like antagonists, we have employed two different approaches: (1) induced fit applied to an apo 3D receptor model, and (2) 3D QSAR. We have applied the Glide/Prime induced fit protocol developed by Schrödinger, using the apo-receptor structure and one of its known antagonists, in order to obtain a 3D receptor-antagonist complex structure. The IF protocol led to a receptor structure able to bind adenosine-like antagonists that can be used in future docking studies. To highlight the spatial arrangement of chemical features that confers drug activity toward the A2A receptor, two different pharmacophore hypotheses were generated with Phase, using 68 A2A antagonists retrieved from literature. Both hypotheses suggested a binding mode consistent with previously published site-directed mutagenesis and SAR studies. The predictive power of these 3D QSAR models is still under development.