Applying polypharmacology approach for drug repurposing for SARS-CoV2

Area of Science:

• Computational drug discovery and virology.
• Exploration of antiviral therapeutics and drug repurposing.

Background:

• The COVID-19 pandemic necessitates pragmatic therapeutic strategies.
• Drug repurposing, particularly polypharmacology, offers an optimized approach to identify effective treatments by targeting multiple viral proteins.
• Seven key SARS-CoV-2 targets were identified for therapeutic intervention.

Purpose of the Study:

• To virtually screen approved drugs for repurposing against critical SARS-CoV-2 targets.
• To identify drug candidates exhibiting polypharmacology by interacting with multiple viral proteins.
• To evaluate the stability and efficacy of potential drug-target interactions.

Main Methods:

• Virtual screening of 4015 approved drugs against seven SARS-CoV-2 targets (3CLpro, PLpro, RdRp, NSP13, NSP14, NSP15, NSP16).
• Molecular docking, molecular dynamics (MD) simulations, and MM-PBSA calculations were employed to assess drug-target interactions.
• Selection criteria included docking score, interaction with at least four targets, and key residue interactions.

Main Results:

• Four drugs—venetoclax, tirilazad, acetyldigitoxin, and ledipasvir—were identified as promising candidates.
• These selected drugs demonstrated favorable docking scores and interacted with multiple SARS-CoV-2 targets.
• MD simulations and MM-PBSA studies confirmed the stability of protein-drug complexes and sustained key interactions.

Conclusions:

• Venetoclax, tirilazad, acetyldigitoxin, and ledipasvir are potential drug repurposing candidates for COVID-19 treatment.
• The study validates the polypharmacology approach for identifying multi-target antiviral agents.
• The findings provide a detailed analysis of protein-drug complexation for seven SARS-CoV-2 targets.