The ligand-based virtual screening of an original chemical library, using atypical antipsychotics as query compounds led to the identification of a novel scaffold with inhibitory activity at the 5-HT2A serotonin receptor. The hit compounds were confirmed by pharmacological evaluation at the 5-HT2A receptor and complemented by the selection of other representatives of the same chemical family within our chemical library. A promising scaffold of 6-(pyperazin-1-yl) purine was identified, and the binding mode is illustrated with an automated docking exploration on a homology built model of the 5-HT2A receptor. The present results constitute an excellent starting point for the discovery of new chemical entities with antipsychotic activity.
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