Artificial neural network‐based quantitative structure–activity relationships model and molecular docking for virtual screening of novel potent acetylcholinesterase inhibitors

Abstract

The deficit in cholinergic neurotransmission is the main incentives for the development of new therapeutic drugs for the treatment of Alzheimer's disease (AD). In this study, we employed cheminformatics tools to explore new molecules that can serve as effective therapeutic agents against AD. Artificial neural networks (ANNs) were applied in a quantitative structure anti‐acetylcholinesterase (AChE)‐activity relationship study on a series of AChE inhibitors (AChEIs). The best computational neural network had an [5‐10‐12‐1] architecture, with a low value of mean squared error (MSE = 0.06) and a high value of R2 (0.96). All validations showed that the ANN model can be used quite satisfactorily for the screening of a new series of molecules having anti‐AChE activity. The virtual screening based on the molecular similarity method and applicability domain of ANN‐quantitative structure–activity relationships allowed the discovery of novel anti‐AChE candidates with improved activity. Docking simulation carried out on these novel AChEIs has identified eight best hits with a higher binding affinity toward their target (4EY7). These eight stable complexes were in good agreement with the biological activity and they have an inhibition profile at a similar rate as the reference drug donepezil. The results showed that these compounds were strongly bound up with the AChE enzyme active site with the optimal conformations.

Structure‐Based Approaches for the Prediction of Alzheimer's Disease Inhibitors: Comparative Interactions Analysis, Pharmacophore Modeling and Molecular Dynamics Simulations

“…This brain lesion is characterized by neurofibrillary tangles arising due to the over-activation of cyclin-dependent kinase 5 (CDK5). [10,12,60] The CDK5 protein and its neuron-specific activator P35 are essential molecules for neuronal migration and the laminar configuration of the cerebral cortex. Activation of calpain is triggered by the increase in intracellular calcium levels induced by Aβ exposure, resulting in cleavage of the P35 regulatory subunit to P10 and P25 subunits.…”

“…Neuronal loss is very strongly correlated with the severity of cognitive deficits in Alzheimer's patients. [12,60,64,67] Therefore, CDK5-type kinases are a promising class of potential targets for the treatment of Alzheimer's disease. [67] Development of a new drug is a risky, expensive, and timeconsuming endeavor.…”

“…Overall, these data demonstrate that over‐activation of CDK5 is associated with hyperphosphorylation of tau, which results in decreased affinity of tau protein and microtubules, which can lead to their destabilization, disrupting axonal transport and ultimately killing neurons leading to neurofibrillary degeneration (TFD). Neuronal loss is very strongly correlated with the severity of cognitive deficits in Alzheimer's patients [12,60,64,67] . Therefore, CDK5‐type kinases are a promising class of potential targets for the treatment of Alzheimer's disease [67] …”

Vehicle Detection and Recognition Approach in Multi-Scale Traffic Monitoring System via Graph-Based Data Optimization

“…This section discusses the ANN approach to classification. An ANN is a collection of multiple perceptrons or neurons on each stratification; when necessary data is categorized in the forward broadcaster, this is known as a feed-forward neural network [ 35 ]. The processing elements, the hidden layers, and the output variable constitute the core structure of an ANN.…”

QSAR Studies and Structure Property/Activity Relationships Applied in Pyrazine Derivatives as Antiproliferative Agents Against the BGC823

“…ANN [67][68][69][70] is a popular nonlinear model, used to predict the biological activity (i.e. IC50) of the datasets of therapeutic molecules.…”