Ptml modeling for alzheimer’s disease: Design and prediction of virtual multi-target inhibitors of GSK3B, HDAC1, and HDAC6

Valeria V. Kleandrova, Alejandro Speck-Planche

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

18 Citas (Scopus)


Background: Alzheimer’s disease is characterized by a progressive pattern of cognitive and functional impairment, which ultimately leads to death. Computational approaches have played an important role in the context of drug discovery for anti-Alzheimer's therapies. However, most of the computational models reported to date have been focused on only one protein associated with Alzheimer's, while relying on small datasets of structurally related molecules. Objective: We introduce the first model combining perturbation theory and machine learning based on artificial neural networks (PTML-ANN) for simultaneous prediction and design of inhibitors of three Alzheimer’s disease-related proteins, namely glycogen synthase kinase 3 beta (GSK3B), histone deace-tylase 1 (HDAC1), and histone deacetylase 6 (HDAC6). Method: The PTML-ANN model was obtained from a dataset retrieved from ChEMBL, and it relied on a classification approach to predict chemicals as active or inactive. Results: The PTML-ANN model displayed sensitivity and specificity higher than 85% in both training and test sets. The physicochemical and structural interpretation of the molecular descriptors in the model permitted the direct extraction of fragments suggested to favorably contribute to enhancing the multi-target inhibitory activity. Based on this information, we assembled ten molecules from several fragments with positive contributions. Seven of these molecules were predicted as triple target inhibitors while the remaining three were predicted as dual-target inhibitors. The estimated physicochemical properties of the designed molecules complied with Lipinski’s rule of five and its variants. Conclusion: This work opens new horizons toward the design of multi-target inhibitors for anti-Alzheimer's therapies.

Idioma originalInglés
Páginas (desde-hasta)1657-1672
Número de páginas16
PublicaciónCurrent Topics in Medicinal Chemistry
EstadoPublicada - 2020
Publicado de forma externa


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