Enhancing the therapeutic potential of FDA-approved ifosfamide and 5-fluorouracil through rational chemical modifications for endometrial cancer treatment.

Abstract

Endometrial or uterine cancers predominantly occur in postmenopausal women, thereby establishing a strong correlation with advanced age. The chemotherapeutic agents ifosfamide and 5-fluorouracil have demonstrated notable efficacy against endometrial cancer by inhibiting cell division and proliferation. Nevertheless, current pharmacological treatments encounter challenges related to drug resistance and adverse effects. To assess the potential of drug modifications, in silico methodologies were employed to alter the molecular structures of ifosfamide and 5-fluorouracil with the aim of enhancing their efficacy and binding affinity to type 1 endometrial cancer. The three-dimensional configurations of mutated KRAS proteins were sourced from the Protein Data Bank. The molecular structures of ifosfamide and 5-fluorouracil were obtained from PubChem and EMBL-EBI, and subsequently modified using Chemsketch. The modifications included the addition of a methyl group, benzene ring, nitrogen atom, cyclopentane ring, and fluorine atoms to the drugs. The binding affinities of these modified drugs to the proteins were visualized using AutoDock Vina. The modified drugs exhibited improved binding affinities of -7.4 and -7.5 kcal/mol with both mutated target proteins. SwissADME analysis and Molinspiration's evaluation of Lipinski's rule parameters suggested that these modified drugs hold promise for the treatment of type 1 endometrial cancer, pending preclinical and clinical trials. This study represents a significant advancement in drug modification as a potential chemotherapeutic strategy for endometrial cancer. Among the two modified drugs, altered 5-fluorouracil demonstrated superior binding affinity and pharmacokinetic properties, rendering it a promising candidate.