Nicotinic cholinergic system and COVID-19: In silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions

Alexandris, Nikolaos; Lagoumintzis, George; Chasapis, Christos T.; Leonidas, D.D.; Παπαδόπουλος, Γεώργιος; Tzartos, Socrates J.; Tsatsakis, Aristidis; Eliopoulos, Elias; Poulas, Konstantinos; Farsalinos, Konstantinos

doi:10.1016/j.toxrep.2020.12.013

Cited by 52 publications

(47 citation statements)

References 60 publications

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“…The target-finding is based on molecular similarities only, without there being any bias toward molecules of relevance to SARS-COV-2. One of the targets found was nicotinic acetylcholine receptor, which was recently reported to be involved in the pathophysiology of SARS-COV-2 [ 14 , 15 ]⁠. Our results show that HCQ binds directly to α7 nicotinic acetylcholine (α7 nAChR) and ACE2 receptors [ 3 ] in a way that would interfere with the binding of the viral spike protein to these receptors⁠.…”

Section: Introductionmentioning

confidence: 71%

“…Only those targets that gave a docking score of −8 kcal/mol or better ( Table 2 a), were pursued further, and these targets are: ACE2, α7 nAChR, α1D-AR, DNA gyrase and HNMT ( Table 2 a). Among the two types of acetylcholine receptors, nAChR was relevant to SARS-COV-2 infection and hence it was taken-up for our studies [ 14 , 15 ]. Many other targets that have given good docking scores with HCQ are found to be directly relevant to SARS-COV-2 infection [ 5 , 13 ]⁠.…”

Section: Resultsmentioning

confidence: 99%

“…Binding of HCQ to ACE2 has the potential to affect viral spike protein binding in two ways: 1) by affecting the glycosylation of ACE2 and 2) by blocking the spike protein binding site on ACE2 [ 44 ]. Interestingly, an equally high docking score is obtained for the target α7 nAChR, which has only recently been shown to be involved in the pathophysiology of SARS-COV-2 [ 14 , 15 ]⁠. The high score for the adrenergic receptor, which is part of the cholinergic pathway, is significant because recently α1D-AR antagonists are found to reduce mortality in COVID-19 patients, and HCQ binding can affect catecholamine signaling pathways during inflammatory cytokine production that is linked to many deaths [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…Based on the observation that the RBD domain of the viral spike protein (SARS-COV-2) contains amino acid sequence motif similar to the known nAChR antagonists, such as α-bungarotoxin, nAChR receptor is suggested as a secondary receptor for SARS-COV-2 entry. This hypothesis suggests not only nAChR mediated virus entry but also dysregulation of the nicotinic cholinergic system (NCS) leading to a cytokine storm along with failure of the immune response to return to homeostasis [ 14 , 15 , 58 , 61 ]⁠. The high docking score of HCQ to α7 nAChR ( Table 2 a) at the toxin binding site (PDB: 3sq9 ) suggests that HCQ may impact nAChR-mediated entry and pathophysiology of SARS-CoV2 [ 59 , 60 ].…”

Section: Resultsmentioning

confidence: 99%

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A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

Navya

Hosur

2021

Informatics in Medicine Unlocked

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COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed a global health emergency. Repurposing of existing drugs can be a rapid and effective strategy to fight the infection. Clinical trials have reported reduction or elimination of viral load when patients were treated with the anti-malarial drug Hydroxychloroquine (HCQ). To understand the molecular mechanism of action for effective repurposing of this drug we have carried out in silico docking and dynamics studies on complexes between HCQ and target proteins, which were identified through both literature survey and structural similarity searches in databases of small molecule – protein complexes. The proteins identified as binding HCQ are: Angiotensin Converting Enzyme 2 (ACE2), α7 nicotinic AcetylCholine Receptor (α7 nAChR), α1D-adrenergic receptor (α1D-AR), Histamine N- Methyl Transferase (HNMT) and DNA gyrase/Topoisomerase III β (Top3β). The majority of these proteins are novel and have not been used before, in docking studies. Our docking and simulation results support action of HCQ both at the entry and post-entry stages of SARS-CoV2 infection. The mechanism of action at the entry stage is through blocking the virus-binding sites on the two receptors, ACE2 & α7 nAChR, by binding directly at those sites. Our computational studies also show that the action of HCQ at the post-entry stage is to prevent both viral replication and generation of ‘cytokine storm’ by inhibiting host Top3β enzyme and α1D-AR, respectively. Binding of HCQ to HNMT is not a desired binding, and therefore this should be reduced during repurposing of HCQ.

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Section: Introductionmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

Navya

Hosur

2021

Informatics in Medicine Unlocked

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“…A further argument to suggest that nicotinic receptor stimulation could be beneficial in COVID-19 is that it could counteract the inhibitory effect of SARS-CoV2 on nicotinic receptors. As a matter of fact, it has been observed the S protein of SARS CoV2 shows sequence analogies with the nAChR blocker α-bungarotoxin ( Kimura et al, 2019 ), and in silico studies showed that it can bind to nAChR and that several nAChR agonists including nicotine can effectively prevent this binding ( Alexandris et al, 2020 ; Lagoumintzis et al, 2021 ). The inhibitory effects of SARS-CoV2 on nAChR are expected to imbalance the equilibrium between Ang II and Ang-(1-7) in favor of the former, hence promoting lung inflammation, whereas cholinergic stimulation could bring back to normal the Ang II/Ang-(1-7) balance.…”

Section: Does the Cholinergic Anti-inflammatory Pathway Regulate Pulmonary Ras Hints From The Covid-19 Pandemics?mentioning

confidence: 99%

The Cholinergic and ACE-2-Dependent Anti-Inflammatory Systems in the Lung: New Scenarios Emerging From COVID-19

et al. 2021

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The renin angiotensin system and the cholinergic anti-inflammatory pathway have been recently shown to modulate lung inflammation in patients with COVID-19. We will show how studies performed on this disease are starting to provide evidence that these two anti-inflammatory systems may functionally interact with each other, a mechanism that could have a more general physiological relevance than only COVID-19 infection.

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New insights on the potential effect of progesterone in Covid‐19: Anti‐inflammatory and immunosuppressive effects

Al‐Kuraishy,

Al‐Maiahy,

Al‐Gareeb

et al. 2023

Immunity Inflam & Disease

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Background: Coronavirus disease 2019 (COVID‐19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS‐CoV‐2). COVID‐19 is higher in men than women and sex hormones have immune‐modulator effects during different viral infections, including SARS‐CoV‐2 infection. One of the essential sex hormones is progesterone (P4). Aims: This review aimed to reveal the association between P4 and Covid‐19. Results and Discussion: The possible role of P4 in COVID‐19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti‐inflammatory cytokines, and inhibition release of pro‐inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti‐inflammatory Th2 with activation release of anti‐inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon‐gamma production that increased during SARS‐CoV‐2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS‐CoV‐2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ‐aminobutyric acid (GABAA) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID‐19 patients. Conclusion: Taken together, the anti‐inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID‐19.

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Nicotinic cholinergic system and COVID-19: In silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions

Cited by 52 publications

References 60 publications

A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

The Cholinergic and ACE-2-Dependent Anti-Inflammatory Systems in the Lung: New Scenarios Emerging From COVID-19

New insights on the potential effect of progesterone in Covid‐19: Anti‐inflammatory and immunosuppressive effects

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