Abstract
We have performed molecular docking on quinazoline antifolates complexed with human thymidylate synthase to gain insight into the structural preferences of these inhibitors. The study was conducted on a selected set of one hundred six compounds with variation in structure and activity. The structural analyses indicate that the coordinate bond interactions, the hydrogen bond interactions, the van der Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. In this study, fast flexible docking simulations were performed on quinazoline antifolates derivatives as human thymidylate synthase inhibitors. The results indicated that the quinazoline ring of the inhibitors forms hydrophobic contacts with Leu192, Leu221 and Tyr258 and stacking interaction is conserved in complex with the inhibitor and cofactor.
Highlights
Thymidylate synthase has been a primary target for chemotherapy aimed at cancers of the gastrointestinal tract and head and neck [1] despite moderate response in 30-40% of patients
To date, several crystal structure of human thymidylate synthase in complex with different inhibitors have been reported viz 1I00 with ternary complex with deoxyuridine 5'-monophosphate (dUMP) and tomudex, [14], 1JUJ with dUMP LY231514, a pyrrolo(2,3-d)pyrimidine-based antifolate [15], 1JTQ with dUMP and the pyrrolo(2,3-d)pyrimidine-based antifolate LY341770 [15], 1JU6 with dUMP and LY231514, a pyrrolo(2,3d)pyrimidine-based antifolate [15], 1HVY with dUMP and raltitrexed, an antifolate drug [16] etc. which provide information about the exact location and composition of inhibitor binding pocket and opportunity to use the enzyme in a functional conformation
Validation of the docking method To ensure that the ligand orientation and the position obtained from the docking studies were likely to represent valid and reasonable binding modes of the inhibitors, the LigandFit program docking parameters had to be first validated for the crystal structure used (PDBid 1I00)
Summary
Thymidylate synthase has been a primary target for chemotherapy aimed at cancers of the gastrointestinal tract and head and neck [1] despite moderate response in 30-40% of patients. A major problem affecting TS-directed treatments is that tumor cells often react to an exposure to Thymidylate synthase inhibitors by raising levels of intracellular TS activity about 2- to 4-fold, which may lead to resistance. The physical structures of bacterial TSs have been relatively well defined, and crystallographic data, in concert with data derived from kinetic, spectroscopic, and site-directed mutagenesis studies, have led to a detailed understanding of the catalytic mechanism of these enzymes [3]. The threedimensional structure of the native human thymidylate synthase (hTS) has been reported previously [4]. Subsequent determination of the structure of a ternary inhibitory complex between closely related ratTS (rTS) and dUMP and tomudex [5] has shown that the ligands bind to the enzyme in the active conformation. The inactive conformation has not been observed in TSs other than human [6]
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