Rational design for novel heterocyclic based Donepezil analogs for Alzheimer’s disease: an in silico approach

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and has devastating impacts on the elderly population. During the last two decades, there has been a significant focus on developing effective and safe treatments for AD. Acetylcholinesterase (AChE) has been identified as one of the primary therapeutic targets for developing drug candidates for AD. However, there is still a need for more efficient therapies. In this study, our aim is to design a new series of heterocyclic-based AChE inhibitors inspired by a standard drug. Here, we carried out molecular docking, drug-likeliness characteristics, and molecular dynamics (MD) to predict important pharmacophore features and understand the inhibitory mechanism of the designed inhibitors towards the AChE. We have designed 112 new derivatives by replacing the piperidine moiety of Donepezil with the different five and six-membered heterocyclic rings and selected 15 compounds that show higher or comparable docking scores as compared to standard Donepezil and pose no risk for carcinogenicity. Furthermore, MD results imply the structural stability of the selected docked complexes and seven exhibit a stronger binding affinity towards the AChE than Donepezil. Thus, heterocyclic-based derivatives based on oxazole, pyrazole, and tetrahydropyran may be potential therapeutic candidates for AD. Our structure-based drug design approach allows us to identify and gain insight into the structural stability of the inhibitor-protein complex and the inhibition mechanism of the newly designed inhibitors. The present finding might be an initial selection for developing a new inhibitor for AD and provide a direction for further experiments on its biological activities.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• heterocyclic compounds
• molecular docking
• molecular dynamics

Acknowledgements

We acknowledge Indian Institute of Technology Patna for providing computational facility to perform the present work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

AS acknowledges GITAM Deemed to be University and DST-FIST Program 2014 (SR/FST/ETI-373/2016).