Lurasidone hydrochloride (LATUDA�), a novel antipsychotic, has potent binding affinity for D2 and 5-HT2A receptors, and negligible affinity for H1 and M1 receptors.  Our previous docking study and structural analysis suggested that lurasidone acquired the high selectivity for the �desired� GPCRs by the combination of the cyclohexyl-linker and the norbornane-2,3-dicarboximide moiety.  In order to validate the previous binding models of lurasidone and gain quantitative insights into the different pharmacological profiles of other antipsychotics, we carried out the calculation of the binding free energy based on the thermodynamics integration method for lurasidone, ziprasidone, and olanzapine to the four GPCRs.  As a result, we obtained good correlation between the calculation and experiment binding free energy for all drug�receptor pairs.  This correlation enables to discuss the difference in the pharmacological profiles of three antipsychotics quantitatively based on the thermodynamics of the drug�receptor interactions with the structural water and the protein flexibility.

Quantitative insights into pharmacological profiles for lurasidone and other antipsychotics by the thermodynamics integration method

244th National Meeting (2012)

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