Designing and computational studies of Novel 5-Fluorouracil hybrids as thymidylate synthase inhibitors for targeting non small cell lung cancer

Cancer is a multifactorial disease characterized by uncontrolled cellular proliferation and impaired regulatory mechanisms, and among its diverse forms, NSCLC remains one of the most prevalent and lethal malignancies worldwide. To address NSCLC, scientists are placing great emphasis on drugs that can reduce cell resistance, improve potency or prevent DNA alterations. Recent studies on TS inhibitors have demonstrated the potential of effective management of NSCLC with minimal adverse reactions. Therefore, there is a demand for more advanced and efficient anti-cancer medications targeting TS inhibitors, as promised in the development of new anti-cancer drugs that have reduced or no adverse effects. The objectives of our recent study were to design and evaluate 5-FU-based hybrids that can inhibit TS in comparison to already known inhibitors such as Raltitrexed. We designed and performed a detailed computational study on 5-FU hybrids, intending to use them as possible inhibitors of TS. After performing various studies on 12 molecules designed, it was found that compounds C04, C08, and C12 presented better results when compared with the standard drug (Raltitrexed). Not only that, but all the designed compounds showed higher stability when compared to the standard drug. Compounds C04, C08 and C12 were chosen for additional screening for molecular studies like Free landscape energy, Principal component analysis, free binding energy study and MD Simulation. Docking investigation utilised the crystal structure of the thymidylate synthase inhibitor enzyme (PDB ID: 6ZXO). Further, MD simulations and QSAR Studies were performed, and satisfactory results were obtained, suggesting future potential drugs for the treatment of NSCLC.