Dual dopamine D₂/5-HT_2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms.  However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk.  In this paper, comparative pharmacophore analysis of dual dopamine D₂/5-HT_2A receptor antagonists, hERG K⁺ channel blockers, and α_1A adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.