In Silico Exploration of Xanthene Aminochloroquinoline Derivatives as Promising Dopamine D2 Receptor Antagonists: ADME, Molecular Docking, DFT Calculations, and MD Simulations

Abstract Schizophrenia is a significant public health challenge, prompting the need for new therapeutic options. This study investigates xanthene aminochloroquinoline derivatives as potential dopamine D2 receptor inhibitors, a target involved in neuropsychiatric disorders like schizophrenia. We employed computational techniques such as molecular docking, molecular dynamics (MD) simulations, density functional theory (DFT), and ADMET analysis to study these 58 derivatives. Our findings show that these compounds exhibit strong binding affinities and stable interactions with the D2 receptor, particularly molecule 15, which demonstrated a binding energy of –13.1 kcal/mol. This value is stronger than that of the reference drug risperidone (–12.1 kcal/mol) and is comparable to the other standard drugs. DFT results indicate favorable solubility and physicochemical properties, supporting their potential as therapeutic agents with dipole moments as high as 15 Debye. Moreover, MD simulation studies further confirmed the stability of the protein–ligand complexes over the simulation period, reinforcing their binding reliability. These combined insights provide a strong basis for further experimental validation and optimization of these compounds for treating dopamine (DA)‐related neuropsychiatric disorders.