Computational insights into KRAS G12C inhibition: exploring possible repurposing of Azacitidine and Ribavirin

Area of Science:

• Oncology
• Computational Biology
• Drug Discovery

Background:

• Kirsten rat sarcoma (KRAS) mutations are prevalent in 22% of cancers, driving tumor initiation and progression.
• Targeting KRAS G12C is crucial for developing effective cancer therapies.
• Repurposing existing drugs offers a promising strategy for treating KRAS-dependent malignancies.

Purpose of the Study:

• To assess the efficacy of 26 nucleoside-based drugs against the KRAS G12C protein.
• To identify potential drug candidates for repurposing in KRAS-dependent cancers.
• To investigate the binding interactions of nucleoside analogs with KRAS G12C using computational methods.

Main Methods:

• In-silico molecular simulations and molecular docking were employed.
• 26 nucleoside-derived drugs were screened against the KRAS G12C protein (PDB ID: 5V71).
• Binding affinities, stability, RMSD, % occupancies, bond angles, and hydrogen bond lengths were analyzed.

Main Results:

• Azacitidine and Ribavirin demonstrated significant binding affinities (-8.7 and -8.3 kcal/mol, respectively).
• These drugs exhibited stable binding to the KRAS G12C active site during simulations.
• Complexes maintained equilibrium with RMSD values between 0.17–0.2 nm, indicating stable interactions.

Conclusions:

• Azacitidine and Ribavirin show potential as candidates for repurposing in KRAS-dependent cancers.
• Computational methods effectively identified promising drug candidates for KRAS G12C.
• Further investigation into these nucleoside analogs could lead to new therapeutic strategies.