title: Pharmacophore-based discovery of new human dihydroorotate dehydrogenase inhibitor.
abstract: Pharmacophore models of human dihydroorotate dehydrogenase (HsDHODH) have been developed using Discovery Studio V2.1 with a training set of 27 HsDHODH inhibitors. With one hydrogen bond receptor, two hydrophobic, one ring aromatic and one neg ionizable features, Hypo 1 has a correlation coefficient of 0.948, cost difference of 78.894, and RMSD 0.926. This model was validated by test set and Fischer randomization test. Hypo 1 was employed as a 3D query to identify potent molecules from our lab chemical database. Compound 38-C11 had Hypo 1 estimated IC50 of 489 nM. Then 38-C11 was synthesized and evaluated in HsDHODH inhibition assay. The IC50 of 38-C11 was 136.9 nM suggesting that 38-C11 could be proceeded for further evaluation in future study.
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.forename: Jinxiong
authors.initials: J
authors.lastname: She
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Mingfang
authors.initials: M
authors.lastname: He
authors.affiliation: Nanjing Sino-USA Cancer Research Center, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing 210009, China. wyb5393@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors