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 deacetylase
1 (HDAC1), and histone deacetylase 6 (HDAC6).
Methods: 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 multitarget
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