Aim: Through the application of structure- and ligand-based methods, the authors aimed to create an integrative approach to developing a computational protocol for the rational drug design of potent dual 5-HT_2A/D₂receptor antagonists without off-target activities on H₁receptors. Materials & methods: Molecular dynamics and virtual docking methods were used to identify key interactions of the structurally diverse antagonists in the binding sites of the studied targets, and to generate their bioactive conformations for further 3D-quantitative structure–activity relationship modeling. Results & conclusion: Toward the goal of finding multi-potent drugs with a more effective and safer profile, the obtained results led to the design of a new set of dual antagonists and opened a new perspective on the therapy for complex brain diseases.