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

Deganutti, Giuseppe; Prischi, Filippo; Reynolds, Christopher A.

doi:10.21203/rs.3.rs-64722/v1

Cited by 8 publications

(7 citation statements)

References 72 publications

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“…As discovered from the crystal structure, K417, Y505 and Q498 in the predicted pocket of RBD interact with the D30, E37 and Q42 of ACE2 respectively. This predicted pocket overlaps with the pocket identified in a recent study by Deganutti et al[ 48 ]. It is plausible that the presence of small drug molecules at the predicted pocket shall interfere the interactions between RBD and human ACE2.…”

Section: Resultssupporting

confidence: 78%

Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations

Kumar

Liu

2021

Computers in Biology and Medicine

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused worldwide pandemic and is responsible for millions of worldwide deaths due to -a respiratory disease known as COVID-19. In the search for a cure of COVID-19, drug repurposing is a fast and cost-effective approach to identify anti-COVID-19 drugs from existing drugs. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein has been a main target for drug designs to block spike protein binding to ACE2 proteins. In this study, we probed the conformational plasticity of the RBD using long molecular dynamics (MD) simulations, from which, representative conformations were identified using clustering analysis. Three simulated conformations and the original crystal structure were used to screen FDA approved drugs (2466 drugs) against the predicted binding site at the ACE2-RBD interface, leading to 18 drugs with top docking scores. Notably, 16 out of the 18 drugs were obtained from the simulated conformations, while the crystal structure suggests poor binding. The binding stability of the 18 drugs were further investigated using MD simulations. Encouragingly, 6 drugs exhibited stable binding with RBD at the ACE2-RBD interface and 3 of them (gonadorelin, fondaparinux and atorvastatin) showed significantly enhanced binding after the MD simulations. Our study shows that flexibility modeling of SARS-CoV-2 RBD using MD simulation is of great help in identifying novel agents which might block the interaction between human ACE2 and the SARS-CoV-2 RBD for inhibiting the virus infection.

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Section: Resultssupporting

confidence: 78%

Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations

Kumar

Liu

2021

Computers in Biology and Medicine

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“…Several aspects of Spike protein dynamics are currently being studied, with a range of particular goals: to evaluate the docking of small molecules to the RBD domain [ 19 ], to search for alternative target binding-sites for vaccine development [ 20 ], to understand residue-residue interactions and their effects on conformational plasticity [ 21 ] and to investigate the flexibility of different domains in particular conformational states [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

2021

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The SARS-CoV-2 Spike protein needs to be in an open-state conformation to interact with ACE2 to initiate viral entry. We utilise coarse-grained normal mode analysis to model the dynamics of Spike and calculate transition probabilities between states for 17081 variants including experimentally observed variants. Our results correctly model an increase in open-state occupancy for the more infectious D614G via an increase in flexibility of the closed-state and decrease of flexibility of the open-state. We predict the same effect for several mutations on glycine residues (404, 416, 504, 252) as well as residues K417, D467 and N501, including the N501Y mutation recently observed within the B.1.1.7, 501.V2 and P1 strains. This is, to our knowledge, the first use of normal mode analysis to model conformational state transitions and the effect of mutations on such transitions. The specific mutations of Spike identified here may guide future studies to increase our understanding of SARS-CoV-2 infection mechanisms and guide public health in their surveillance efforts.

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“…In addition to virtual screening techniques, all-atomistic (16,17) and coarse-grained (18)(19)(20) molecular dynamics (MD) methods are effective computational tools for multiscale modeling of virus infection process and computer-aided drug design (21). Deganutti et al (22) employed structure-based screening and supervised MD to find potential drugs that can bind to the druggable pockets of the RBD and inhibit the binding process. They reported Cefsulodin and Nilotinib as the potential disruptors of the ACE2-RBD interface.…”

Section: Introductionmentioning

confidence: 99%

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study

Razizadeh

Nikfar

Liu

2021

Biophysical Journal

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The ongoing COVID-19 pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the SARS-CoV-2 mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host cell receptor, angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate the RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the meta-stable, pre-fusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, molecular docking was employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex were analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.

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

Cited by 8 publications

References 72 publications

Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations

Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations

Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study

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