In silico design and evaluation of novel 5-fluorouracil analogues as potential anticancer agents

5-fluorouracil (5-FU) has been shown to have suffered from resistance which demands a solution entailing the development of 5-FU analogues. Our study aims to design a number of analogues of 5-FU and evaluate their effectiveness against thymidylate synthase (TS) in silico compared to parent 5-FU with an effort to obtain better hit(s). All the molecules were optimized by molecular mechanics method utilizing MM2 forcefield parameters. Molecular docking of these molecules against TS was performed to catch on the binding strength of these molecules, determination of binding energy & interaction types of each ligand-target complex as well as subsequent analysis. PRA10 showed highest binding affinity (-9.1 Kcal/mol). Although binding energy of PRA6 & PRA14 are slightly lower than PRA10, they can be of special interest since they interact with crucial amino acids for binding and exhibit substantial non-bonded interactions. Residue analysis revealed that Arg50A, Arg175B, Arg215A, Ser216A, Arg176B and Asn226A of TS active site were crucial for binding/interaction. The best scored drug candidates demonstrated considerable pharmacokinetic as well as druglike properties. The present study also revealed that PRA6, PRA10 and PRA14 can be potential anticancer drugs for further development.