Development of dual inhibitors against Alzheimer's disease using fragment-based QSAR and molecular docking.

Manisha Goyal,Rabia Hamid,Chetna Tyagi,Abhinav Grover,Sukriti Goyal,Jaspreet Kaur Dhanjal

doi:10.1155/2014/979606

Abstract

Alzheimer's (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression. β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BACE-1 and AChE. The GQSAR model provides site-specific clues about the molecules where certain modifications can result in increased biological activity. This information could be of high value for design and development of multifunctional drugs for combating AD.

Highlights

Alzheimer’s disease (AD) is an irreversible chronic brain disorder among elderly people [1,2,3]
The experimentally reported inhibitory activity [IC50] of all the 20 compounds was converted into pIC50 [−log10 IC50], which was subsequently used as response or dependent variable for group-based quantitative structure activity relationship- (QSAR) (GQSAR) model building
We have attempted to identify a novel GQSAR model depicting robust statistical correlation between structure and activity of DHP analogues which have been reported as potent suppressors of BACE-1

Summary

Introduction

Alzheimer’s disease (AD) is an irreversible chronic brain disorder among elderly people [1,2,3]. AD is characterized by steady cognitive impairment, memory loss, and decline in language. It is one of the leading causes of death in the world. It was estimated that 5.2 million Americans of all ages were suffering from AD in 2013 making it the sixth leading cause of death in the United States (Alzheimer’s association; http://www.alz.org/). The devastating pathological hallmarks of AD are extracellular accumulation of neurotoxic amyloid β (Aβ) peptides [4], loss of the presynaptic markers of the cholinergic system in the brain, mitochondrial dysfunction, and formation of dense neurofibrillary tangles of hyperphosphorylated tau protein in the central nervous system [5,6,7].

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Conclusion