title: QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors.
abstract: Aurora kinases have emerged as attractive targets for the development of novel anti-cancer agents. A combined study of molecular docking, pharmacophore modelling and 3D-QSAR was performed on a series of imidazo [1, 2-a] pyrazines as novel Aurora kinase inhibitors to gain insights into the structural determinants and their structure-activity relationship. An ensemble of conformations based on molecular docking was used for PHASE pharmacophore studies. The developed best-fitted pharmacophore model was validated by diverse chemotypes of Aurora A kinase inhibitors and was consistent with the structural requirements for the docked binding mechanism. Subsequently, the pharmacophore-based alignment was used to develop PHASE and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models. The best CoMSIA model showed good statistics (q (2 )= 0.567, r (2 )= 0.992), and the predictive ability of the model was validated using an external test set of 13 compounds giving a satisfactory prediction ([Formula: see text]). The 3D contour maps provided insight into the binding mechanism and highlighted key structural features that are essential to the inhibitory activity. Based on the PHASE and CoMSIA 3D-QSAR results, a set of novel Aurora A inhibitors were designed that showed excellent potencies.
authors.affiliation: Laboratory of Molecular Design and Drug Discovery, School of Basic Science, China Pharmaceutical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Leng
authors.forename: T
authors.initials: T
authors.lastname: Lu
authors.forename: H L
authors.initials: HL
authors.lastname: Yuan
authors.forename: H C
authors.initials: HC
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.forename: W W
authors.initials: WW
authors.lastname: Zhang
authors.forename: Y L
authors.initials: YL
authors.lastname: Jiang
authors.forename: Y D
authors.initials: YD
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D064127:Aurora Kinases; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011719:Pyrazines; C556838:imidazo(1,2-a)pyrazine; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases