title: PLS and shape-based similarity analysis of maleimides--GSK-3 inhibitors.
abstract: BACKGROUND
  Glycogen synthase kinase-3 (GSK-3) overactivity was correlated with several pathologies including type 2 diabetes mellitus, Alzheimer's disease, cancer, inflammation, obesity, etc.
  
  
  OBJECTIVE
  The aim of the current investigation was to model the inhibitory activity of maleimide derivatives--inhibitors of GSK-3, to evaluate the impact of alignment on statistical performances of the Quantitative Structure-Activity Relationship (QSAR) and the effect of the template on shape-similarity--binding affinity relationship.
  
  
  METHODS
  Dragon descriptors were used to generate Projection to Latent Structures (PLS) models in order to identify the structural prerequisites of maleimides to inhibit GSK-3. Additionally, shape/volume structural analysis of binding site interactions was evaluated.
  
  
  RESULTS
  Reliable statistics R(2)(Y(CUM)) = 0.938/0.920, Q((2)(Y)(CUM)) = 0.866/0.838 for aligned and alignment free QSAR models and significant (Pearson, Kendall and Spearman) correlations between shape/volume similarity and affinities were obtained.
  
  
  CONCLUSIONS
  The crucial structural features modulating the activity of maleimides include topology, charge, geometry, 2D autocorrelations, 3D-MoRSE as well as shape/volume and molecular flexibility.
authors.affiliation: Department of Computational Chemistry, Institute of Chemistry of Romanian Academy , Timisoara , Romania .
authors.forename: Luminita
authors.initials: L
authors.lastname: Crisan
authors.forename: Liliana
authors.initials: L
authors.lastname: Pacureanu
authors.forename: Sorin
authors.initials: S
authors.lastname: Avram
authors.forename: Alina
authors.initials: A
authors.lastname: Bora
authors.forename: Speranta
authors.initials: S
authors.lastname: Avram
authors.forename: Ludovic
authors.initials: L
authors.lastname: Kurunczi
mesh_terms: D062313:Databases, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008301:Maleimides; C043592:maleimide; D038362:Glycogen Synthase Kinase 3
keywords: Pose prediction; QSAR; ROCS; rank correlation