Thymidylate synthase is the important enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair.. Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme Thymidylate synthase and have potential as an anti-colorectal cancer chemotherapy. Pyridine and Pyrimidine derivatives are found to be the potent inhibitors of Thymidylate synthase enzyme were rapidly identified. The molecular modeling aspects of the pyridine and pyrimidine derivatives are also presented.