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

Area of Science:

• Computational biology
• Drug discovery
• Virology

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, necessitates rapid identification of effective treatments.
• Drug repurposing offers a cost-effective strategy for discovering anti-COVID-19 agents.
• The SARS-CoV-2 spike protein's receptor binding domain (RBD) is a key target for blocking viral entry into host cells via ACE2.

Purpose of the Study:

• To investigate the conformational flexibility of the SARS-CoV-2 RBD using molecular dynamics (MD) simulations.
• To identify potential drug candidates for COVID-19 by screening FDA-approved drugs against dynamic RBD conformations.
• To evaluate the binding stability of identified drug candidates using MD simulations.

Main Methods:

• Long molecular dynamics (MD) simulations were performed to probe the conformational plasticity of the SARS-CoV-2 RBD.
• Clustering analysis was used to identify representative RBD conformations from the simulations.
• A library of 2466 FDA-approved drugs was screened against the ACE2-RBD interface using docking simulations on both crystal and simulated conformations.

Main Results:

• MD simulations revealed significant conformational flexibility in the SARS-CoV-2 RBD.
• Screening identified 18 potential drug candidates, with 16 derived from simulated conformations, outperforming the crystal structure.
• Further MD simulations confirmed stable binding for 6 drugs, with 3 (gonadorelin, fondaparinux, atorvastatin) showing significantly enhanced binding stability.

Conclusions:

• Flexibility modeling of the SARS-CoV-2 RBD using MD simulations is crucial for effective drug repurposing.
• This approach successfully identified novel drug candidates that could inhibit SARS-CoV-2 infection by blocking ACE2-RBD interaction.
• The identified drugs, particularly gonadorelin, fondaparinux, and atorvastatin, warrant further investigation as potential COVID-19 therapeutics.