Molecular Dynamics and Electron Density Topology Reveal Ligand-Specific Interaction Patterns at the Dopamine D2 Receptor

Abstract

The dopamine D2 receptor (D2R) is one of the principal therapeutic targets for the treatment of schizophrenia and other neuropsychiatric disorders. Understanding how ligands with different pharmacological profiles interact with D2R is essential for the rational design of safer and more effective antipsychotic drugs. In this work, Molecular Dynamics (MD) simulations combined with Quantum Theory of Atoms in Molecules (QTAIM) analysis were employed to investigate the electronic nature of protein–ligand interactions in D2R embedded in a neuronal membrane environment. Representative agonists (dopamine and rotigotine) and antipsychotics from different generations (haloperidol, risperidone, and aripiprazole) were analyzed to identify interaction patterns associated with distinct pharmacological activities. The agonist-bound simulations revealed recurrent interactions involving the serine-rich region, whereas the antipsychotic-bound systems exhibited more persistent contacts within the central aromatic region of the binding pocket. These observations suggest ligand-associated interaction tendencies rather than universal determinants of agonism or antagonism. Furthermore, aripiprazole displayed a unique interaction profile characterized by enhanced coupling with the PIF connector, suggesting a distinct modulation of the TM6 toggle switch compared with other antipsychotics. The integration of MD and electron density topology revealed ligand-specific interaction networks associated with distinct pharmacological profiles at D2R. The interaction patterns identified in this study highlight characteristic interaction motifs associated with ligand-specific pharmacological profiles and provide mechanistic insights that may support the rational design of novel dopaminergic therapeutics.