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

International Journal of Molecular Sciences

Felipe Dias Leal²  Camilo Henrique da Silva Lima²  Ricardo Bicca de Alencastro²  Helena Carla Castro³  Carlos Rangel Rodrigues¹  Magaly Girão Albuquerque² 

[1] Faculdade de Farmácia, Laboratório de Modelagem Molecular & 3D-QSAR (ModMolQSAR), Universidade Federal do Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil; E-Mail:;Instituto de Química, Laboratório de Modelagem Molecular (LabMMol), Universidade Federal do Rio de Janeiro (UFRJ), 21949-900 Rio de Janeiro, RJ, Brazil; E-Mails:;Instituto de Biologia, Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol), Universidade Federal Fluminense (UFF), 24210-130 Niterói, RJ, Brazil; E-Mail:

关键词: Alzheimer’s disease;    molecular hologram;    HQSAR;    molecular modeling;    DYRK1A inhibitors;   

DOI  :  10.3390/ijms16035235

来源: mdpi

【 摘 要 】

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; SE_cv = 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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.