Hologram QSAR Models of 4-[(Diethylamino)methyl]-phenol Inhibitors of Acetyl/Butyrylcholinesterase Enzymes as Potential Anti-Alzheimer Agents

Simone Decembrino De Souza,Lúcio Mendes Cabral,Ana Carolina Rennó Sodero,Magaly Girão Albuquerque,Ana Carolina Corrêa De Sousa,Helena Carla Castro,Carlos Rangel Rodrigues,Alessandra Mendonça Teles De Souza

doi:10.3390/molecules17089529

Simone Decembrino De Souza, Lúcio Mendes Cabral + Show 6 more

Open Access

https://doi.org/10.3390/molecules17089529

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Abstract

Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer’s disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0. 904) and non-cross-validated (AChE, r2 = 0.965; BChE, r2 = 0.952) correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people
A data set of 36 4-[(diethylamino)methyl]-phenol AChE/BChE inhibitors was compiled from the work of Yu et al [16]
The data set used for the hologram quantitative structure-activity relationship (HQSAR) studies contains the 36 4-[(diethylamino)methyl]-phenol derivatives developed by Yu et al, showing cholinesterase inhibitory activity against both AChE and

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people. As the worldwide population ages, AD is reaching epidemic levels, giving rise to a huge human, social, and economic burden [1,2]. The main therapeutic approaches in AD treatment are based on the cholinergic hypothesis According to this hypothesis, the neurodegenerative processes lead to a selective destruction of the cholinergic neurons, resulting in a lack of central cholinergic transmission. The symptomatic treatment of AD is based on acetylcholinesterase (AChE) inhibitors, which have positive effects on the cognitive, functional, and behavior symptoms of the disease and increase acetylcholine levels and cholinergic neurotransmission in the brain [8]. In an attempt to design new chemical entities with efficient anticholinesterase activities, we have explored the 2D molecular features of a series of 4-(diethylamino)methyl]-phenol AChE/BChE inhibitors [16] using the HQSAR method, a powerful ligand-based strategy in drug design [17]

HQSAR Analysis

Data Set and Molecular Modeling

Conclusions