In Silico Identification of Hydroxyxanthone Derivatives as CDK2/EGFR Dual Inhibitor for Colorectal Cancer Treatment

Both CDK2 (cyclin-dependent kinase 2) and EGFR (epidermal growth factor receptor) play significant roles in the development and progression of colorectal cancer. In vitro studies of several hydroxyxanthone derivatives for the treatment of WiDr cancer cell lines have revealed potential anticancer activity against colorectal cancer. The present study aims to identify hydroxyxanthone derivatives as potential drug candidates for colorectal cancer treatment through an in silico approach.

Interactions between seven hydroxyxanthone (X1-X7) derivatives and CDK2 and EGFR were analyzed using molecular docking, molecular dynamics simulations, and binding energy calculations based on the MM-PBSA method. We also evaluated the physicochemical properties and ADMET profiles using the pkCSM server.

Docking studies demonstrated that all hydroxyxanthone derivatives exhibited favorable binding affinities, ranging from -7.25 to -8.57 kcal/mol against CDK2 and -6.79 to -8.31 kcal/mol against EGFR. Following 200 ns molecular dynamics simulations, compounds X4, X5, and X7 showed higher structural stability than doxorubicin and comparable stability to the native ligands C62 and erlotinib. Consistently, MM/PBSA analysis revealed that X4 (-20.27 kcal/mol) and X7 (-25.29 kcal/mol) achieved the most favorable binding free energies for CDK2 and EGFR, respectively. Moreover, these compounds satisfied Lipinski's criteria and met the minimum requirements for ADMET drug-likeness parameters.

Hydroxyxanthone derivatives X4, X5, and X7 exhibit the strongest potential as dual CDK2/EGFR inhibitors and may, therefore, serve as promising candidates for colorectal cancer therapy. Nevertheless, further in vitro and in vivo investigations are required to experimentally validate their therapeutic potential.