Research Projects

Human thymidylate synthase is a rate-limiting enzyme throughout the de novo synthesis of 2'-deoxythymidine-5'-monophosphate in the DNA synthesis pathway, provides an essential nucleotide for genome integrity and cellular economics. By using Methylene tetrahydrofolate as a donor of methyl group, it catalyses the reductive methylation of dUMP (deoxyUridine monophosphate) to dTMP (deoxyThymidine monophosphate) (Fig. 1). dUMP (Pyrimidine) and folate binding site hTs inhibitors showed resistance in colorectal cancer (CRC) by overexpression of Ts. In the present proposal, Based on structural characteristics of the pyrido[2,3-d]pyrimidine database, new pyrido[2,3-d]pyrimidine analogues were discovered by virtual screening, binding free energy calculations, and pharmacophore mapping studies. The designed Ts inhibitors will be synthesized using the synthetic procedure described in the methodology section and characterized by using various spectral techniques like IR, 1H & 13C NMR, HRMs, and elemental analysis. The synthesized compounds will be tested in vitro for their cytotoxicity and kinase inhibitory assay for their Ts inhibitory potential and then subjected to in vivo activity in AOM or Dss induced mice model. In silico studies like ADMET or PK-PD, sAR or QsAR, molecular simulations will also be performed on lead inhibitors for further refinement.