The 3D-QSAR analysis of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains on thymidylate synthase

Thymidylate synthase (TS) is a critical enzyme for DNA biosynthesis and many nonclassical lipophilic antifolates targeting this enzyme are quite efficient and encouraging as antitumor drug. In this paper, the binding model of 14 antifolates of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains was examined using molecular simulation methods--FlexiDock and SCORE2.0. The resulted conformation and orientation of these antifolates were directly applied to CoMFA study. A good correlation between the calculated binding energies of these antifolates complexed with TS and their inhibitory activities was derived. The robust QSAR model, its three-dimensional contour map, and binding score for these antifolates derived from SCORE2.0 provided guidelines for structural optimization of current antifolates.