A Repurposed Drug Screen Identifies Compounds That Inhibit the Binding of the COVID-19 Spike Protein to ACE2

Tsegay, Kaleb B.; Adeyemi, Christiana M.; Gniffke, Edward P.; Sather, D. Noah; Walker, John K.; Smith, Stephen

doi:10.3389/fphar.2021.685308

Cited by 14 publications

(19 citation statements)

References 45 publications

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“…We identified four clusters (A, B, C, and D) in our pharmacophore search of the FDA-approved drug database containing more than ten compounds (18, 18, 14, and 11 correspondingly); three clusters (E, F, and G) containing eight, six, and five compounds correspondingly; three clusters (H, I, and J) with four compounds; three clusters (K, L, and M) with three compounds; and eight two-compound clusters (N-R and T-V) and 35 3. 27 To validate the search results and select the best binding drugs, we docked the conformers from the set of 152 drugs selected from the pharmacophore-based search and from a set of 100 random compounds to the binding site of the ACE2 receptor (Protein Data Bank entry, 6VW1).…”

Section: Pharmacophore-based Docking Resultsmentioning

confidence: 99%

Potential SARS-CoV-2 Spike Protein-ACE2 Interface Inhibitors: Repurposing FDA-approved Drugs

Kouznetsova¹,

Zhang²,

Miller³

et al. 2021

J Explor Res Pharmacol

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Background and objectives:The SARS-CoV-2 virus Spike (S) protein binds to an angiotensin-converting-enzyme 2 receptor (ACE2) on the surface of cells to allow viral DNA entry. Given the plenitude of FDA-approved antiviral drugs, we aimed to screen those that may be repurposed for treating SARS-CoV-2 infections.Methods: Using the crystal structure of SARS-CoV-2 Spike complexed with ACE2 (PDB ID: 6VW1) as a template, we developed a pharmacophore model of functional centers of the SARS-CoV-2 Spike protein inhibitor-binding domain. The conformations of these compounds underwent 3D fingerprint similarity clusterization, followed by docking of possible conformers to the binding site of ACE2. A similar protocol was followed for a set of randomlyselected compounds. Molecular dynamics was perform to confirm the stability of the selected drugs bound to ACE2.Results: Based on the model, we conducted a pharmacophore search from a conformational database of FDAapproved drugs. From the 379 compounds identified as potential inhibitors of SARS-CoV-2, 152 compounds with the best scores were selected based on maximal hydrogen-bond and hydrophobic interactions. The average free energies of the docking interaction for the selected compounds were better than those of random compounds. The obtained drug list includes inhibitors of HIV, HCV, CMV, ZIKV, HMPV, and RVFV as well as a set of drugs that have demonstrated some activity in MERS, SARS-CoV, and SARS-CoV-2 therapy.Conclusions: Using a set of computational methods, we predicted the FDA-approved drugs that might bind to the interface of ACE2 protein and Spike protein of SARS-CoV-2 and prevent binding between Spike and ACE2. In further works, we recommend testing the selected compounds for treatment of COVID-19.

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Section: Pharmacophore-based Docking Resultsmentioning

confidence: 99%

Potential SARS-CoV-2 Spike Protein-ACE2 Interface Inhibitors: Repurposing FDA-approved Drugs

Kouznetsova¹,

Zhang²,

Miller³

et al. 2021

J Explor Res Pharmacol

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“…From our virtual screening of FDA approved molecules, these pockets are druggable and accommodates several small molecules including irinotecan, ergotamine, nilotinib, and ponatinib. For example, nilotinib was shown to reduce SARS-CoV-2 infection by ~50% ( Cagno et al, 2021 ), likely via blocking spike interactions with ACE2 ( Tsegay et al, 2021 ). Notably, top-ranked molecules ( Supplementary file 1E ) were also predicted to bind RBD in the previous virtual screening studies ( Deganutti et al, 2020 ; Murugan et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein

Dokainish¹,

Mori³

et al. 2022

eLife

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Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-EM structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down to one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.

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“…Importantly, carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19 ( 67 ). Consistently, in screening 2,701 compounds from a commercial library of drugs that potentially block the interaction between the S protein and ACE2, oxytocin is among four best candidates along with thiostrepton, nilotinib, and hydroxycamptothecin ( 68 ). This proposal is also in agreement with the view that oxytocin may be repurposed as an agent for treatment of the COVID-19 patients ( 98 – 100 ).…”

Section: Covid-19 and Endocrine Activitymentioning

confidence: 99%

“…Moreover, oxytocin has the potential to block the viral entry directly or through regulating the secretion of other hormones. As stated above, oxytocin is one of the four compounds that strongly inhibit binding of SARS-CoV-2 to ACE2 ( 68 ). Oxytocin may reduce viral entry through influencing estrogen secretion ( 94 ).…”

Section: Therapeutic and Preventive Potential Of Oxytocin Against Of ...mentioning

confidence: 99%

Potential of Endogenous Oxytocin in Endocrine Treatment and Prevention of COVID-19

et al. 2022

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Coronavirus disease 2019 or COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant threat to the health of human beings. While wearing mask, maintaining social distance and performing self-quarantine can reduce virus spreading passively, vaccination actively enhances immune defense against COVID-19. However, mutations of SARS-CoV-2 and presence of asymptomatic carriers frustrate the effort of completely conquering COVID-19. A strategy that can reduce the susceptibility and thus prevent COVID-19 while blocking viral invasion and pathogenesis independent of viral antigen stability is highly desirable. In the pathogenesis of COVID-19, endocrine disorders have been implicated. Correspondingly, many hormones have been identified to possess therapeutic potential of treating COVID-19, such as estrogen, melatonin, corticosteroids, thyroid hormone and oxytocin. Among them, oxytocin has the potential of both treatment and prevention of COVID-19. This is based on oxytocin promotion of immune-metabolic homeostasis, suppression of inflammation and pre-existing comorbidities, acceleration of damage repair, and reduction of individuals’ susceptibility to pathogen infection. Oxytocin may specifically inactivate SARS-COV-2 spike protein and block viral entry into cells via angiotensin-converting enzyme 2 by suppressing serine protease and increasing interferon levels and number of T-lymphocytes. In addition, oxytocin can promote parasympathetic outflow and the secretion of body fluids that could dilute and even inactivate SARS-CoV-2 on the surface of cornea, oral cavity and gastrointestinal tract. What we need to do now is clinical trials. Such trials should fully balance the advantages and disadvantages of oxytocin application, consider the time- and dose-dependency of oxytocin effects, optimize the dosage form and administration approach, combine oxytocin with inhibitors of SARS-CoV-2 replication, apply specific passive immunization, and timely utilize efficient vaccines. Meanwhile, blocking COVID-19 transmission chain and developing other efficient anti-SARS-CoV-2 drugs are also important. In addition, relative to the complex issues with drug applications over a long term, oxytocin can be mobilized through many physiological stimuli, and thus used as a general prevention measure. In this review, we explore the potential of oxytocin for treatment and prevention of COVID-19 and perhaps other similar pathogens.

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A Repurposed Drug Screen Identifies Compounds That Inhibit the Binding of the COVID-19 Spike Protein to ACE2

Cited by 14 publications

References 45 publications

Potential SARS-CoV-2 Spike Protein-ACE2 Interface Inhibitors: Repurposing FDA-approved Drugs

Potential SARS-CoV-2 Spike Protein-ACE2 Interface Inhibitors: Repurposing FDA-approved Drugs

The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein

Potential of Endogenous Oxytocin in Endocrine Treatment and Prevention of COVID-19

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