Blocking Coronavirus 19 Infection via the SARS-CoV-2 Spike Protein: Initial Steps

Whisenant, Jonathan; Burgess, Kevin

doi:10.1021/acsmedchemlett.0c00233

Cited by 30 publications

(28 citation statements)

References 8 publications

(11 reference statements)

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“…An intriguing way to tackle the SARS-CoV-2 infection is to disrupt the entrance of the virus into host cells by blocking the molecular machinery implied in this fundamental step [36,62,70,73]. The structural basis of the interaction between ACE2 and the S glycoprotein RBD (Figure 1) could drive the discovery of small molecules and monoclonal antibodies [8,52,66] able to slow down, or even prevent, the development of COVID-19 [7,27,39,74].…”

Section: Introductionmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

Preprint

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The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting the importance of considering the dynamic formation of the heterodimer when judging any potential candidate.

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Section: Introductionmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Different therapeutic strategies could be envisaged. On one hand, drugs could bind to the RBD, as is the case for small peptides 29 − 31 and neutralizing monoclonal antibodies. 32 Nevertheless, possible mutations of the RBD may decrease the efficiency of a treatment based on this approach.…”

mentioning

confidence: 99%

Thermodynamics of the Interaction between the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus-2 and the Receptor of Human Angiotensin-Converting Enzyme 2. Effects of Possible Ligands

García‐Iriepa

Hognon

Francés‐Monerris

et al. 2020

J. Phys. Chem. Lett.

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Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 1000000 deaths all over the world and still lacks a medical treatment despite the attention of the whole scientific community. Human angiotensin-converting enzyme 2 (ACE2) was recently recognized as the transmembrane protein that serves as the point of entry of SARS-CoV-2 into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the protein complex. Moreover, the free energy of binding between ACE2 and the active receptor binding domain of the SARS-CoV-2 spike protein is evaluated quantitatively, providing for the first time the thermodynamics of virus–receptor recognition. Furthermore, the action of different ACE2 ligands is also examined in particular in their capacity to disrupt SARS-CoV-2 recognition, also providing via a free energy profile the quantification of the ligand-induced decreased affinity. These results improve our knowledge on molecular grounds of the SARS-CoV-2 infection and allow us to suggest rationales that could be useful for the subsequent wise molecular design for the treatment of COVID-19 cases.

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Section: Introductionmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

J Comput Aided Mol Des

View full text Add to dashboard Cite

The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.

show abstract

Blocking Coronavirus 19 Infection via the SARS-CoV-2 Spike Protein: Initial Steps

Abstract: Recent crystal structure data for protein–protein interactions featuring the SARS-CoV-2 spike protein will inevitably trigger a new wave of research in this area that was not possible before. This Viewpoint outlines a few of the ways that it is already happening.

Cited by 30 publications

References 8 publications

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Thermodynamics of the Interaction between the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus-2 and the Receptor of Human Angiotensin-Converting Enzyme 2. Effects of Possible Ligands

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

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