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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Molecular docking and dynamics analysis of flavonoids from Retama monosperma with drug-resistant GIST mutations

Kaoutar El Khattabi1, Jihane Akachar1, Sanaa Lemriss2

  • 1Medical Biotechnology Laboratory, Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Rabat, Morocco.

Bioinformation
|February 7, 2025
PubMed

Insights

Luteolin, a natural flavonoid, shows promise in overcoming tyrosine kinase inhibitor resistance in gastrointestinal stromal tumors (GISTs). This compound effectively targets key mutations, offering a potential new therapeutic strategy for GIST treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Computational Chemistry

Background:

  • Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract.
  • Activating mutations in c-Kit and PDGFRα are primary drivers of GIST development.
  • Resistance to tyrosine kinase inhibitors (TKIs) presents a significant clinical challenge, necessitating novel therapeutic approaches.

Purpose of the Study:

  • To investigate the potential of Luteolin, a flavonoid from Retama monosperma, as a therapeutic agent against GIST.
  • To evaluate Luteolin's binding affinities and interactions with c-Kit and PDGFRα, including resistant mutations.
  • To assess Luteolin's drug-likeness and stability through computational methods.

Main Methods:

  • Molecular docking simulations were employed to assess binding affinities of Luteolin to c-Kit and PDGFRα.
  • Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties were predicted.
  • Molecular dynamic simulations were conducted over 100 ns to evaluate complex stability.
  • Binding affinities to specific resistant mutations (c-Kit D816H, PDGFRα T674I) were analyzed.

Main Results:

  • Luteolin demonstrated high binding affinities for both PDGFRα (-8.1 kcal/mol) and c-KIT (-9.6 kcal/mol), comparable to approved TKIs.
  • The compound exhibited favorable ADMET properties and formed significant hydrogen and hydrophobic interactions with target residues.
  • Molecular dynamics simulations confirmed stable Luteolin-target complexes.
  • Luteolin showed strong binding and enhanced stability against resistant GIST mutations (c-Kit D816H, PDGFRα T674I).

Conclusions:

  • Luteolin possesses significant potential as a dual inhibitor of c-Kit and PDGFRα.
  • Its ability to target resistant mutations suggests it could be a promising alternative to conventional TKIs for GIST treatment.
  • Natural compounds like Luteolin warrant further investigation for novel cancer therapies.
Keywords:
Gastrointestinal stromal tumorsRetama monospermaflavonoidsmolecular dockingmolecular dynamics simulations

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