In silico methods reconfiiin CDK2 as a potential molecular target of 5-fluorouracil

The extensive use of 5-fluorouracil (5-FU) in chemotherapy has given rise to drug-resistance. The fact that some compounds have shown additive and/or synergistic effects with 5-fluorouracil has led to the exploration of combination therapy. This has triggered the quest for computer aided design and screening of molecular targets for 5-FU based on Molecular Dynamics simulations. The current study was undertaken with the objective of designing and screening compounds which can serve as putative targets for 5-FU using 'in silico reverse screening' techniques and evaluation of their ligand-binding properties with 5-FU. The identification of molecular target was achieved employing two pharmacophore screening servers, namely, PharmMapper and PharmaGist. The potential targets were selected after virtual screening, and their efficiency was compared with 5-FU based on docking analyses. This led to the identification of novel targets which were further evaluated based on free energy calculations by molecular dynamics simulations. The molecular dynamics based analysis revealed that cell division protein kinase 2 (CDK2) can act as molecular target for 5-FU. It also showed a binding affinity towards 5-FU which was comparable with human thymidine phosphorylase, a well-studied 5-FU target. Therefore, CDK2 in combination with 5-FU has great potential to be used of in chemotherapy.