title: The 3D-QSAR analysis of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains on thymidylate synthase.
abstract: 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.
authors.affiliation: The Key Laboratory of Chemical Biology, Guangdong Province, Graduate School at Shenzhen, Tsinghua University, China.
authors.forename: Shiying
authors.initials: S
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yu
authors.forename: Guoyu
authors.initials: G
authors.lastname: Ding
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D003198:Computer Simulation; D005493:Folic Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D052999:Quinazolinones; D013859:Thiocarbamates / Q000737:chemistry*; D013940:Thymidylate Synthase / Q000187:drug effects / Q000378:metabolism*
chemical_list: D005493:Folic Acid Antagonists; D011799:Quinazolines; D052999:Quinazolinones; D013859:Thiocarbamates; C061339:4-hydroxyquinazoline; D013940:Thymidylate Synthase