Virtual Screening of a Marine Natural Product Database for In Silico Identification of a Potential Acetylcholinesterase Inhibitor

Author:

Gade Anushree Chandrashekhar1,Murahari Manikanta2ORCID,Pavadai Parasuraman3,Kumar Maushmi Shailesh1ORCID

Affiliation:

1. Somaiya Institute of Research and Consultancy, Somaiya Vidyavihar University, Mumbai 400077, India

2. Department of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India

3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru 560054, India

Abstract

Alzheimer’s disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future.

Funder

DST-SERB

Publisher

MDPI AG

Subject

Paleontology,Space and Planetary Science,General Biochemistry, Genetics and Molecular Biology,Ecology, Evolution, Behavior and Systematics

Reference33 articles.

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5. (2023, March 23). FDA, Available online: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease.

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