The dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The previously developed D2HighR and D2LowR dimeric models by our group are used to investigate the prediction of binding affinity of LY404,039 ligand and its binding mechanism within the catalytic domain. The obtained computational data using molecular dynamics (MD) simulations fits well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2HighR and D2LowR targets were -12.04 and -9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to the D2HighR and D2LowR with 8.2 and 1640 nM binding affinities (Ki), respectively. The high binding affinity of LY404,039 in terms of binding to [3H]domperidone was inhibited by the presence of guanine nucleotide, indicating an agonist action of the drug at D2HighR. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2HighR binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2LowR. Molecular modeling analyses are extended to ensemble docking as well as structure-based pharmacophore model (E-Pharmacophore) development using the bioactive conformation of LY404,039 at the binding pocket as template and screening of small-molecule databases with derived pharmacophore models.