Modification of 5-fluorouracil with thiourea and benzoyl groups and in silico study on thymidylate synthase enzyme as an anticancer candidate

Context: Cancer remains the leading cause of death worldwide, so new therapeutic strategies are needed. 5-Fluorouracil (5-FU) has been widely used in chemotherapy, but its effectiveness is limited by side effects and drug resistance. Recent research focuses on modifying 5-FU to improve its anticancer properties, specifically through structural modifications using thiourea and benzoyl groups. Aims: To design a modified 5-FU derivative with a thiourea and benzoyl group and evaluate its potential as an anticancer agent targeting the enzyme thymidylate synthase. A computational approach is used to predict the pharmacokinetic properties, toxicity, and affinity of the binding of these compounds. Methods: A total of 81 5-FU derivatives were synthesized and evaluated using the in silico method. The ligand was designed and protonated at a physiological pH of 7.4 using MarvinSketch software. Molecular docking simulations were performed using PyRx, and the five best compounds simulated molecular dynamics using Desmond software to assess the stability of the ligand-receptor complex. Pharmacokinetic and toxicity profiles are predicted using the pkCSM web server. Results: The docking study identified the five best compounds with better binding affinity than standard 5-FU. Among these compounds, FUBT-81 has the lowest binding energy of -8.82 kcal/mol. Molecular dynamics simulations showed that FUBT-55 had the most stable interaction with thymidylate synthase, indicated by the lowest RMSD and RMSF values during the 100 ns simulation. Conclusions: Modified 5-FU derivatives, especially FUBT-55, exhibit better binding stability and affinity to thymidylate synthase, making them potentially more effective anticancer agents. These findings support advanced studies in vitro and in vivo to validate their effectiveness and safety.