In order to improve the treatment of Parkinson´s disease and Schizophrenia, one of the proposed strategies has been the development of subtype selective ligands targeting D2 and D3 dopamine receptors. An essential advance for this type of strategy was the recent crystallographic elucidation of the human dopamine D3 receptor structure in complex with the antagonist eticlopride, which revealed important features of the ligand-binding pocket. Taking this new crystallographic data into account, we have performed a quantum biochemistry investigation of the eticlopride binding to D3 in order to estimate the individual contribution of the most important amino acid residues at the binding pocket. Such estimates were obtained using the molecular fractionation with conjugate caps approach within the framework of density functional theory using both the local density and generalized gradient approximations. Our simulations showed that the total interaction energy of eticlopride bound to D3 as a function of the binding pocket size stabilizes only when residues within a radius of at least 8.0 Å from the drug centroid are taken into account. The strongest drug-residue interaction energy was observed for Asp110 followed, among others, by Phe345, Phe346, Ile183, Val107, Tyr373, Val189, Trp342, Cys114 and Val82, the later being a repelling residue which was not considered to be important in the original crystallographic data analysis. Our results highlight the key amino acid residues involved in the binding of antipsychotics to D3R and could be useful for future studies on the binding of different antagonists to members of the dopamine receptor family.

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