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Int. J. Mol. Sci. 2015, 16(3), 5235-5253; doi:10.3390/ijms16035235

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

1
Instituto de Química, Laboratório de Modelagem Molecular (LabMMol), Universidade Federal do Rio de Janeiro (UFRJ), 21949-900 Rio de Janeiro, RJ, Brazil
2
Instituto de Biologia, Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol), Universidade Federal Fluminense (UFF), 24210-130 Niterói, RJ, Brazil
3
Faculdade de Farmácia, Laboratório de Modelagem Molecular & 3D-QSAR (ModMolQSAR), Universidade Federal do Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editor: Habil. Mihai V. Putz
Received: 9 December 2014 / Revised: 5 February 2015 / Accepted: 10 February 2015 / Published: 6 March 2015
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
View Full-Text   |   Download PDF [1075 KB, uploaded 6 March 2015]   |  

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. View Full-Text
Keywords: Alzheimer’s disease; molecular hologram; HQSAR; molecular modeling; DYRK1A inhibitors Alzheimer’s disease; molecular hologram; HQSAR; molecular modeling; DYRK1A inhibitors
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Leal, F.D.; da Silva Lima, C.H.; de Alencastro, R.B.; Castro, H.C.; Rodrigues, C.R.; Albuquerque, M.G. 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. Int. J. Mol. Sci. 2015, 16, 5235-5253.

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