version date: 1 December 2006 common to active molecules, such as hydrogen bond donors and acceptors, positively or negatively charged groups, and hydrophobic groups of an appropriate size. The correlation of these structures with pharmacological action and complementary molecular interaction analyses between biological molecules and substrate/drug were possible by the use of a web accessible tool, Protein Explorer, a freeware option under PDb view Structure. The steps involved in the manipulation of Protein Explorer are described in the supplemental material The students are asked to render different format and color 3D enzymes from PDB and search the Display File list to access the catalytic site. Although some target enzyme active sites are not available from PDB files, it is possible to estimate how strongly a molecule will bind to a catalytic site by selecting the ligands surface contacts favorably interacting with specific functional groups of both ligand and macromolecule(see supplemental material). TS(group I)and dhfR (group VIl) are conveniently chosen enzymes to illustrate these tutorials due to their concomitant action in the cell de novo biosynthesis of thymidilate nucleotides Both enzymes have long been recognized as a drug target for inhibiting DNA synthesis in rapidly proliferating cells such as cancer cells or in bacterial or malarial infections. Traditional inhibitors clinically used as antineoplastic and antimicrobial agents, have been modeled on dUMP or the cofactor N, N-methylenetetrahydrofolate, and thus are structurally related to natural substrate and cofactor 3] Thymidylate synthase Backs ground Thymidylate synthase catalyzes the reductive methylation of 2 -deoxyuridine monophosphate (dUMP)to 2 -deoxythymidylate monophosphate(dTMP), using N, NO. methylenetetrahydrofolate cofactor, which is concomitantly converted to 7, 8-dihydrofolate <www.iupac.org/publications/cd/medicinalchemistry/> 1010 common to active molecules, such as hydrogen bond donors and acceptors, positively or negatively charged groups, and hydrophobic groups of an appropriate size. The correlation of these structures with pharmacological action and complementary molecular interaction analyses between biological molecules and substrate/drug were possible by the use of a web accessible tool, Protein Explorer, a freeware option under PDB View Structure. The steps involved in the manipulation of Protein Explorer are described in the supplemental material. The students are asked to render different format and color 3D enzymes from PDB and search the Display File list to access the catalytic site. Although some target enzyme active sites are not available from PDB files, it is possible to estimate how strongly a molecule will bind to a catalytic site by selecting the ligand’s surface contacts favorably interacting with specific functional groups of both ligand and macromolecule (see supplemental material). TS (group I) and DHFR (group VII) are conveniently chosen enzymes to illustrate these tutorials due to their concomitant action in the cell de novo biosynthesis of thymidilate nucleotides. Both enzymes have long been recognized as a drug target for inhibiting DNA synthesis in rapidly proliferating cells such as cancer cells or in bacterial or malarial infections. Traditional inhibitors clinically used as antineoplastic and antimicrobial agents, have been modeled on dUMP or the cofactor N5 ,N10-methylenetetrahydrofolate, and thus are structurally related to natural substrate and cofactor [3]. Thymidylate synthase Background Thymidylate synthase catalyzes the reductive methylation of 2'-deoxyuridine monophosphate (dUMP) to 2'-deoxythymidylate monophosphate (dTMP), using N5 ,N10- methylenetetrahydrofolate cofactor, which is concomitantly converted to 7,8-dihydrofolate <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006