Thymidylate kinase (TMK) is a potential chemotherapeutic target since it is directly involved in the synthesis of deoxythymidine 5’-triphosphate an essential component in DNA replication. Inhibiting the function of TMK blocks DNA synthesis in replicating organisms. We report 3D-QSAR analysis on a series of thymidine mimetics exhibiting potent inhibitory activity against TMK. Molecular docking, Comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) were carried out to determine the requisite 3D structural features required for potent thymidylate kinase inhibitory activity. The molecules were divided into training set and test set, a PLS analysis was performed and QSAR models were generated. The model showed good statistical reliability which is evident from the q2loo, r2ncv and r2pred. The models were graphically interpreted using CoMFA and CoMSIA contour maps. The results obtained from this study were used for rational design of potent inhibitors against thymidylate kinase.
Thymidylate kinase, Thymidine triphosphate, Thymidine mimetics, Molecular docking, Comparative molecular field analysis, Comparative similarity indices analysis