title: In silico identification of structure requirement for novel thiazole and oxazole derivatives as potent fructose 1,6-bisphosphatase inhibitors.
abstract: Fructose 1,6-bisphosphatase (FBPase) has been identified as a drug discovery target for lowering glucose in type 2 diabetes mellitus. In this study, a large series of 105 FBPase inhibitors were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in potency. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r(ncv) (2), q(2) values of 0.986, 0.514 for internal validation, and r(pred) (2), r(m) (2) statistics of 0.902, 0.828 statistics for external validation. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules. (1) Substituents with a proper length and size at the C5 position of the thiazole core are required to enhance the potency; (2) A small and electron-withdrawing group at the C2 position linked to the thiazole core is likely to help increase the FBPase inhibition; (3) Substituent groups as hydrogen bond acceptors at the C2 position of the furan ring are favored. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential FBPase inhibitors.
authors.affiliation: Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116023, China; E-Mails:  dluthm@yeah.net  (M.H.);  zswei@dlut.edu.cn  (S.Z.).
authors.forename: Ming
authors.initials: M
authors.lastname: Hao
authors.forename: Xiaole
authors.initials: X
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Luo
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Ji
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010080:Oxazoles; D013844:Thiazoles; D006597:Fructose-Bisphosphatase