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

Abstract

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. Electronic supplementary material The online version of this article (10.1007/s00109-020-01980-1) contains supplementary material, which is available to authorized users.

Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: an integrated computational approach

“…The three-dimensional coordinates of protein structures were taken from the Protein Data Bank ( www.rcsb.org ) [ 40 ]. The co-crystalized X-ray structure of SARS-CoV-2 spike receptor with ACE2 (PDB ID: 6M0J) [ 41 ], 3-chymotrypsin-like cysteine protease (3CL pro ) (PDB ID: 6M2N), CTSL (PDB ID: 6F06) [ 41 ], crystal structure of nucleocapsid protein (PDB ID: 6M3M) [ 36 ], RdRp (PDB ID: 6M71) [ 42 ], non-structural protein 6 (NSP6) [ 39 , 43 ] and cryo–electron microscopy structure of RdRp enzyme with remdesivir and NSP12-NSP7-NSP8 complex (PDB ID: 7BV2) [ 14 ] were taken as the targets for the virtual screening of selected FDA-approved antiviral agents as shown in the supporting information, Supplementary Figure S1 available online at https://academic.oup.com/bib .…”

Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy

“… In vitro, In vivo and clinical trials should be done to confirm the activity [ 96 , 97 , 120 , 121 ] Hydroxychloroquine Anti-malarial drug with sigma-1 receptor agonist activity In vitro and some small uncontrolled studies suggested its efficacy in preventing SARS CoV-2 infection N/A Clinical studies showed little benefit to hospitalized patients treated with hydroxychloroquine which, however, could increase the risk of death in SARs CoV-2 hospitalized patients [ 123 , 126–130 ] PB28 Antagonist of the sigma-1 receptor Prevent the severity of SARS-CoV-2 infection PB28 binds to the Sigma-InsP3 receptor complex results in modulation of NSP6 activity leading to autophagosome activation In vitro, In vivo and clinical trials should be done to confirm the activity [ 61 , 133–135 ] Haloperidol Antipsychotic drug with sigma-1 (antagonist) and sigma-2 activity (agonist) Limit the severity of SARS-CoV-2 infection. Docking studies suggest haloperidol could effectively bind with NSP6 Activation of NSP6 could lead to activation of autophagy Clinical study has indicated that haloperidol treatment does not change the associated risk of intubation or death compared to patients not treated with haloperidol, nor does it affect time to discharge [ 61 , 136 , 137 ] Chlorpromazine Neuroleptic drug with sigma-1 receptor activity Prevent the severity of SARS-CoV-2 infection in monkey and human cells and in some patients Unknown Very few SARS-CoV-2 patients have taken chlorpromazine and more studies should be done [ 138 , 139 ] …”

“…Gordon et al, has identified haloperidol as a drug that could limit the severity of SARS-CoV-2 infection, inhibiting SARS-CoV-2 with K i of 2–12 nM [ 61 ]. Furthermore, docking analysis of haloperidol with the NSP6 protein shows haloperidol binds with an affinity score of −7.7 kcal/mol, which predicts a K D in the nano to the micromolar range [ 136 ]. However, it should be noted that an initial observational clinical study has indicated that haloperidol treatment does not change the associated risk of intubation or death compared to patients not treated with haloperidol, nor does it affect time to discharge [ 137 ].…”

SARS-CoV-2: From the pathogenesis to potential anti-viral treatments

“…SARS-CoV-2 NSP6, infects both organelles by binding to the sigma receptor in the ER membrane [129] , [130] . Haloperidol, which has been used to treat people with psychosis, has recently gained attention due to its anti-inflammatory role in the treatment of COVID-19.…”

“…However, the conflicting results and biphasic activity led to the drug being further investigated. Pandey et al determined the molecular mechanism of both drugs haloperidol and dextromethorphan using computational bioinformatics methods that only proved the inhibitory effects of haloperidol SARS-CoV-2 [129] .…”