Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity? Insights from All-Atom Simulations

Spinello, Angelo; Saltalamacchia, Andrea; Magistrato, Alessandra

doi:10.1021/acs.jpclett.0c01148

Cited by 161 publications

(273 citation statements)

References 32 publications

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“…A further SuMD replica reproduced the complex with good agreement to the cryo-EM structure ( Figure S6a), while other two simulations were not productive after 230 ns ( Figure S6b,c). SuMD reproduced the stability and intermolecular contacts observed between the RBD and ACE2 during MD of the PDB structure 6M17 (Figure 3a,b), highlighting RBD site 1 residues T500, Y505, N501, and Q498 as the most involved in interactions alongside Q493, L455, K417 (site 2) and F486 (site 3) [5,60,63].…”

Section: Cefsulodin Cromoglycate Nafamostat Nilotinib Pen Uridol mentioning

confidence: 58%

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: Cefsulodin Cromoglycate Nafamostat Nilotinib Pen Uridol mentioning

confidence: 58%

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

Deganutti

Prischi

Reynolds

2020

Preprint

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“… 17 Molecular modeling and simulation studies have also been performed to rationalize, at the atomistic level, the behavior of the different involved proteins, 18 the pattern of interactions between them and other biological structures such as nucleic acids, 19 and the inherent differences between the SARS-CoV-2 proteome and those of other coronaviruses, such as SARS-CoV or the Middle East respiratory syndrome (MERS) agents. 20 …”

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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“…For instance, Smith et al [7] have scanned thousands of ligands with molecular dynamics simulations of the RBD, and have ranked these ligands based on their affinity. Other studies have focused their attention on quantifying the S-protein/ACE2 receptor's formation energy, using a full trimeric model and/or a single Sprotein/ACE2 receptor [8][9][10][11]. While these studies provide useful information on the compound's formation energy, they failed in predicting realistic interaction energies that can be indirectly contrasted with experimental measurements.…”

Section: Introductionmentioning

confidence: 99%

Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

Ponga

2020

Preprint

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The binding affinity and adhesive strength between the spike (S) glycoproteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 (ACE2) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is e RS = 12.6 ± 1 kCal∙mol-1 with a maximum adhesive force of ~102 pN. Our analysis suggests that only 27 (13 in S-protein, 14 in ACE2) residues are active during the initial fusion process between the S-protein and ACE2 receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50% or more, to block SARS-CoV-2 particles with radius in the order of R≤60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins and receptors for the development of new therapeutics treatments for COVID-19 guided by computational design.

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Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity? Insights from All-Atom Simulations

Cited by 161 publications

References 32 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

Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

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