Antipsychotic haloperidol binding to the human dopamine D3 receptor: beyond docking through QM/MM refinement toward the design of improved schizophrenia medicines.

As the dopamine D3R receptor is a promising target for schizophrenia treatment, an improved understanding of the binding of existing antipsychotics to this receptor is crucial for the development of new potent and more selective therapeutic agents. In this work, we have used X-ray cocrystallization data of the antagonist eticlopride bound to D3R as a template to predict, through docking essays, the placement of the typical antipsychotic drug haloperidol at the D3R receptor binding site. Afterward, classical and quantum mechanics/molecular mechanics (QM/MM) computations were employed to improve the quality of the docking calculations, with the QM part of the simulations being accomplished by using the density functional theory (DFT) formalism. After docking, the calculated QM improved total interaction energy EQMDI = -170.1 kcal/mol was larger (in absolute value) than that obtained with classical molecular mechanics improved (ECLDI = -156.3 kcal/mol) and crude docking (ECRDI = -137.6 kcal/mol) procedures. The QM/MM computations reveal the pivotal role of the Asp110 amino acid residue in the D3R haloperidol binding, followed by Tyr365, Phe345, Ile183, Phe346, Tyr373, and Cys114. Besides, it highlights the relevance of the haloperidol hydroxyl group axial orientation, which interacts with the Tyr365 and Thr369 residues, enhancing its binding to dopamine receptors. Finally, our computations indicate that functional substitutions in the 4-clorophenyl and in the 4-hydroxypiperidin-1-yl fragments (such as C3H and C12H hydrogen replacement by OH or COOH) can lead to haloperidol derivatives with distinct dopamine antagonism profiles. The results of our work are a first step using in silico quantum biochemical design as means to impact the discovery of new medicines to treat schizophrenia.