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The outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus continually led to infect a large population worldwide. SARS-CoV-2 utilizes its NSP6 and Orf9c proteins to interact with sigma receptors that are implicated in lipid remodeling and ER stress response, to infect cells. The drugs targeting the sigma receptors, sigma-1 and sigma-2, have emerged as effective candidates to reduce viral infectivity, and some of them are in clinical trials against COVID-19. The antipsychotic drug, haloperidol, exerts remarkable antiviral activity, but, at the same time, the sigma-1 benzomorphan agonist, dextromethorphan, showed pro-viral activity. To explore the potential mechanisms of biased binding and activity of the two drugs, haloperidol and dextromethorphan towards NSP6, we herein utilized molecular docking-based molecular dynamics simulation studies. Our extensive analysis of the protein-drug interactions, structural and conformational dynamics, residual frustrations, and molecular switches of NSP6-drug complexes indicates that dextromethorphan binding leads to structural destabilization and increase in conformational dynamics and energetic frustrations. On the other hand, the strong binding of haloperidol leads to minimal structural and dynamical perturbations to NSP6. Thus, the structural insights of stronger binding affinity and favorable molecular interactions of haloperidol towards viral NSP6 suggests that haloperidol can be potentially explored as a candidate drug against COVID-19. KEY MESSAGES: •Inhibitors of sigma receptors are considered as potent drugs against COVID-19. •Antipsychotic drug, haloperidol, binds strongly to NSP6 and induces the minimal changes in structure and dynamics of NSP6. •Dextromethorphan, agonist of sigma receptors, binding leads to overall destabilization of NSP6. •These two drugs bind with NSP6 differently and also induce differences in the structural and conformational changes that explain their different mechanisms of action. •Haloperidol can be explored as a candidate drug against COVID-19.

Insights into the biased activity of dextromethorphan and haloperidol towards SARS-CoV-2 NSP6: in silico binding mechanistic analysis