Molecular docking and dynamics analysis of flavonoids from Retama monosperma with drug-resistant GIST mutations.

Abstract

Gastrointestinal stromal tumors (GISTs), the most prevalent mesenchymal tumors of the gastrointestinal tract, are predominantly driven by activating mutations in receptor tyrosine kinases such as c-Kit and PDGFRα. Resistance to tyrosine kinase inhibitors (TKIs) poses a substantial therapeutic challenge, underscoring the need for novel treatments. Consequently, investigating the potential of natural compounds, specifically flavonoids from Retama monosperma, known for their diverse bioactivities, is of significant interest. Molecular docking and simulations revealed that Luteolin exhibited high binding affinities for PDGFRα (-8.1 kcal/mol) and c-KIT (-9.6 kcal/mol), comparable to Avapritinib and Sunitinib. The compound demonstrated favorable ADMET properties and formed notable hydrogen bonds and hydrophobic interactions with key residues in both targets. Molecular dynamic simulation over 100 ns revealed stable complexes with consistent RMSD and RMSF values. Additionally, Luteolin showed strong binding affinities to the resistant mutations c-Kit (D816H) and PDGFRα (T674I), with enhanced stability. These findings suggest that Luteolin has significant potential as a dual inhibitor and offers a promising alternative to conventional TKIs for addressing GIST resistance.