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

Abstract

Mutations in the c-KIT or PDGFRα genes primarily drive gastrointestinal stromal tumors (GISTs). While tyrosine kinase inhibitors (TKIs) such as Imatinib have improved outcomes, resistance due to secondary mutations remains a significant challenge. This study used computational methods to identify phytochemicals from Moroccan plants as dual inhibitors of c-KIT and PDGFRα. Screening 545 phytochemicals, 6-Hydroxygenistein (6-OHG), a derivative of Genistein, showed high binding affinities (-10.3 kcal/mol for PDGFRα and -10.5 kcal/mol for c-KIT), comparable to Imatinib. 6-OHG demonstrated competitive binding affinities, favorable ADMET properties, good solubility, and oral bioavailability. Its antioxidant properties suggest a potentially lower toxicity profile. Interaction analysis revealed significant hydrogen bonds and hydrophobic interactions with key residues in both targets. Molecular dynamics simulations over 30 ns indicated stable complexes with consistent RMSD values, radius of gyration, solvent-accessible surface area, and hydrogen bonding patterns. Free binding energy calculations using the MM-PBSA method highlighted strong binding efficacy, with total binding energies of -278.0kcal/mol for PDGFRα and -202.1kcal/mol for c-KIT, surpassing Imatinib. These findings suggest that 6-OHG is a promising dual inhibitor for GIST therapy, potentially overcoming resistance mechanisms associated with current TKIs. However, further experimental validation is necessary to fully understand it's potential.