Unveiling the Anticancer Properties of Xanthone Derivatives: Molecular Docking, Molecular Dynamics simulation, MM-PBsA calculation, and Pharmacokinetics Prediction

This investigation evaluates the potential of xanthone derivatives to inhibit cyclin-dependent kinases (CDK2) and epidermal growth factor receptor (EGFR) through molecular docking, molecular dynamics simulation, binding energy analysis using MM-PBSA, and ADMET predictions. Molecular docking results revealed that the binding energies of all xanthone derivatives (X1-X6) ranged between -6.69 and -7.39 kcal/mol for the CDK2 protein and -6.25 to -6.85 kcal/mol for the EGFR protein. Furthermore, a 50-nanoseconds molecular dynamics simulation showed that the root mean square deviation (RMSD) of 1-(dimethylamino)-3,4,6-trihydroxy-9H-xanthen-9-one (X3) and 3,4,6-trihydroxy-2-mercapto-9H-xanthen-9-one (X4) maintained stable interactions within the protein's active site. The root mean square fluctuation (RMSF) analysis indicated that these xanthone derivatives exhibited similar amino acid fluctuation patterns to the native ligands (C62 and erlotinib), suggesting comparable binding interactions. Binding energy assessments via MM-PBSA demonstrated that 1-(dimethylamino)-3,4,6-trihydroxy-9H-xanthen-9-one (X3) and 3,4,6-trihydroxy-2-mercapto-9H-xanthen-9-one (X4) had lower binding energies than the native ligands (C62 and erlotinib) and doxorubicin. Additionally, these compounds adhered to Lipinski's rule and met the minimum requirements in ADMET property predictions. In conclusion, 1-(dimethylamino)-3,4,6-trihydroxy-9H-xanthen-9-one (X3) and 3,4,6-trihydroxy-2-mercapto-9H-xanthen-9-one (X4) demonstrate significant potential as therapeutic candidates for cancers associated with CDK2 and EGFR dysregulation, warranting further research and development.