Antipsychotic Haloperidol Binding to the Human Dopamine D3 Receptor: Beyond Docking Through QM/MM Refinement Toward the Design of Improved Schizophrenia Medicines

Abstract

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.

Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs

“…Most studies agree on the region in which haloperidol binds in the OBS; however, there is not consensus on the orientation of the molecule, which diverges by 180° 24 . The most recent evidence from quantum mechanics 25 , molecular dynamics 24 and experimental studies point to a binding mode with the butyrophenone moiety binding deep in the binding cavity 26 , in agreement with our docking prediction. The experiments suggest that the affinity of 3 is mainly affected by mutations C114 3.36 L, I183 ECL2 F and E90 2.65 Q (Fig.…”

Vitamin B6 and Its Role in Cell Metabolism and Physiology

“…Epinephrine is critical for acute stress responses ( fight-or-flight response ) in humans [ 141 ] and is classically used as a medication for anaphylaxis, a severe allergic reaction, or cardiac arrest [ 142 , 143 ]. Dopamine can be considered a ‘reward’ neurotransmitter that can regulate positive emotions but also motoric control, and it has been associated with Parkinson’s disease and schizophrenia [ 144 , 145 , 146 , 147 , 148 ]. Serotonin (or 5-hydroxytryptamine) is known as a neurotransmitter that helps patients with depression by promoting well-being and contentment [ 149 , 150 , 151 ].…”

Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies

“…This valuable finding may lead to the instructive development of the quantitative structure-activity relationship (QSAR) model. QM/MM simulation has also been utilized to improve the quality of the docking results of human dopamine D3 receptor (D3R), which has been identified as an antipsychotic drug target for schizophrenia treatment [33,34]. The well-known atypical antipsychotic (AAP) drugs include risperidone, aripiprazole, ziprasidone, clozapine, olanzapine, and quetiapine.…”