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Molecular docking analysis reveals differential binding affinities of multiple classes of selective inhibitors

Sai Charitha Mullaguri1, Sravani Akula1, Partha Sarathi Sahoo2

  • 1Molecular Medicine and Therapeutics Laboratory, CPMB, Osmania University, Hyderabad, 500007 India.

3 Biotech
|November 10, 2022
PubMed

Insights

RAS inhibitors show varied effectiveness against KRAS-mutated cancers. This study uses molecular docking to predict drug responses, revealing differential sensitivities and resistance patterns for KRAS-non-G12C mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Computational Chemistry

Background:

  • KRAS mutations are common in solid tumors, driving cancer development.
  • Targeting KRAS-G12C mutations with specific inhibitors has shown clinical success.
  • Predicting responses for other KRAS mutations (non-G12C) to RAS inhibitors remains challenging due to limited data.

Observation:

  • This study evaluated the sensitivity of various KRAS-non-G12C mutations to approved and experimental RAS inhibitors.
  • Molecular docking simulations were employed to predict binding energies and infer drug sensitivity.
  • Computational predictions were validated against limited existing experimental data.

Findings:

  • Molecular docking effectively predicted the sensitivity of KRAS mutants to RAS inhibitors, aligning with experimental results.
  • Significant differential sensitivity was observed among KRAS mutants against both clinical and experimental inhibitors.
  • Some KRAS mutants displayed broad cross-resistance, while others showed resistance to specific inhibitors.

Implications:

  • The findings highlight the potential for developing drug resistance mutations in KRAS-mutated cancers.
  • This research underscores the need for novel RAS inhibitors capable of overcoming primary and secondary drug resistance.
  • The molecular docking approach provides a valuable tool for predicting patient response to RAS-targeted therapies.
Keywords:
AdagrasibDrug sensitivityKRAS proteinNon-G12C mutationsRAS inhibitorsSotorasib

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