Molecular docking and simulation analysis of c-KIT and PDGFRα with phytochemicals as dual inhibitors for GIST

Area of Science:

• Computational drug discovery
• Oncology
• Pharmacology

Background:

• Gastrointestinal stromal tumors (GISTs) are primarily driven by c-KIT or PDGFRα mutations.
• Tyrosine kinase inhibitors (TKIs) like Imatinib have improved GIST treatment but face challenges with drug resistance due to secondary mutations.

Purpose of the Study:

• To computationally identify novel phytochemicals from Moroccan plants with dual inhibitory activity against c-KIT and PDGFRα.
• To evaluate the potential of identified compounds as GIST therapeutics, aiming to overcome existing resistance mechanisms.

Main Methods:

• Virtual screening of 545 phytochemicals against c-KIT and PDGFRα.
• Molecular docking, molecular dynamics simulations (30 ns), and MM-PBSA calculations.
• Assessment of binding affinities, ADMET properties, solubility, and oral bioavailability.

Main Results:

• 6-Hydroxygenistein (6-OHG) exhibited high binding affinities for both PDGFRα (-10.3 kcal/mol) and c-KIT (-10.5 kcal/mol), comparable to Imatinib.
• 6-OHG demonstrated favorable ADMET properties, good solubility, oral bioavailability, and potent antioxidant activity.
• Molecular dynamics and binding energy calculations confirmed stable interactions and superior binding efficacy compared to Imatinib.

Conclusions:

• 6-Hydroxygenistein (6-OHG) is a promising dual inhibitor of c-KIT and PDGFRα with potential therapeutic applications for GISTs.
• 6-OHG may offer a strategy to overcome resistance associated with current TKIs.
• Further experimental validation is required to confirm the therapeutic potential of 6-OHG in GIST treatment.