title: Hologram QSAR models of a series of 6-arylquinazolin-4-amine inhibitors of a new Alzheimer's disease target: dual specificity tyrosine-phosphorylation-regulated kinase-1A enzyme.
abstract: Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A) is an enzyme directly involved in Alzheimer's disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based) models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test) of DYRK1A. The best HQSAR model (q2 = 0.757; SEcv = 0.493; R2 = 0.937; SE = 0.251; R2pred = 0.659) presents high goodness-of-fit (R2 > 0.9), as well as high internal (q2 > 0.7) and external (R2pred > 0.5) predictive power. The fragments that increase and decrease the biological activity values were addressed using the colored atomic contribution maps provided by the method. The HQSAR contribution map of the best model is an important tool to understand the activity profiles of new derivatives and may provide information for further design of novel DYRK1A inhibitors.
authors.affiliation: Instituto de Química, Laboratório de Modelagem Molecular (LabMMol), Universidade Federal do Rio de Janeiro (UFRJ), 21949-900 Rio de Janeiro, RJ, Brazil. felipedleal@gmail.com.
authors.forename: Felipe Dias
authors.initials: FD
authors.lastname: Leal
authors.affiliation: Instituto de Química, Laboratório de Modelagem Molecular (LabMMol), Universidade Federal do Rio de Janeiro (UFRJ), 21949-900 Rio de Janeiro, RJ, Brazil. camilolima@iq.ufrj.br.
authors.forename: Camilo Henrique
authors.initials: CH
authors.lastname: da Silva Lima
authors.affiliation: Instituto de Química, Laboratório de Modelagem Molecular (LabMMol), Universidade Federal do Rio de Janeiro (UFRJ), 21949-900 Rio de Janeiro, RJ, Brazil. bicca@iq.ufrj.br.
authors.forename: Ricardo Bicca
authors.initials: RB
authors.lastname: de Alencastro
authors.affiliation: Instituto de Biologia, Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol), Universidade Federal Fluminense (UFF), 24210-130 Niterói, RJ, Brazil. hcastrorangel@yahoo.com.br.
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
authors.affiliation: Faculdade de Farmácia, Laboratório de Modelagem Molecular & 3D-QSAR (ModMolQSAR), Universidade Federal do Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil. rangel@pharma.ufrj.br.
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: Instituto de Química, Laboratório de Modelagem Molecular (LabMMol), Universidade Federal do Rio de Janeiro (UFRJ), 21949-900 Rio de Janeiro, RJ, Brazil. magaly@iq.ufrj.br.
authors.forename: Magaly Girão
authors.initials: MG
authors.lastname: Albuquerque
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000737:chemistry; D000097603:Dyrk Kinases
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D000097603:Dyrk Kinases