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

• Published in: International journal of molecular sciences 2015-03, Vol.16 (3), p.5235-5253
• Main Authors: Leal, Felipe Dias, da Silva Lima, Camilo Henrique, de Alencastro, Ricardo Bicca, Castro, Helena Carla, Rodrigues, Carlos Rangel, Albuquerque, Magaly Girão
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Amines - chemistry; Amines - metabolism; Amines - therapeutic use; Drug therapy; Dyrk Kinases; DYRK1A inhibitors; Enzymes; HQSAR; Humans; Inhibitor drugs; Kinases; molecular hologram; molecular modeling; Phosphorylation; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Quantitative Structure-Activity Relationship; Quinazolines - chemistry
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms16035235

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.