Computer-Aided Discovery of Natural Compounds Targeting the ADAR2 dsRBD2-RNA Interface and Computational Modeling of...

Area of Science:

• Computational chemistry and drug discovery
• Oncology and cancer therapeutics
• Molecular biology and RNA-binding proteins

Background:

• Mesothelioma is an aggressive cancer with poor prognosis, often linked to asbestos exposure.
• Inhibiting adenosine deaminase acting on dsRNA 2 (ADAR2) RNA binding shows promise for mesothelioma treatment.
• Limited effective treatments currently exist for mesothelioma.

Purpose of the Study:

• To identify natural compounds from Traditional Chinese Medicine (TCM) that can bind to and inhibit ADAR2's RNA-binding domain (dsRBD2).
• To assess the drug-likeness, safety, and binding affinity of these compounds.
• To develop high-quality ADAR2 models for further research.

Main Methods:

• Molecular docking of TCM compounds to ADAR2 dsRBD2.
• Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations for binding affinity.
• Molecular dynamics (MD) simulations to analyze protein-ligand-RNA interactions.
• Development of full-length ADAR2 models.

Main Results:

• Eight compounds exhibited high binding affinity to ADAR2 dsRBD2.
• Four compounds (ZINC000085597263, ZINC000085633079, ZINC000014649947, ZINC000034512861) showed negative binding affinities in the presence of the RNA substrate.
• Key residues (Val164, Met165, Lys209, Lys212) were identified as crucial for ligand binding, suggesting inhibition of ADAR2 RNA binding.
• Predicted biological activities and structural similarities to known anticancer agents suggest therapeutic potential for mesothelioma.

Conclusions:

• Identified natural compounds have the potential to inhibit ADAR2 RNA binding, offering a novel therapeutic strategy for mesothelioma.
• These compounds, structurally related to existing anticancer drugs, warrant further investigation and optimization for mesothelioma treatment.
• The developed ADAR2 models provide valuable insights for future protein engineering and therapeutic development.