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Virtual screening of acetylcholinesterase inhibitors through pharmacophore-based 3D-QSAR modeling, ADMET, molecular docking, and MD simulation studies

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Abstract

Alzheimer’s disease (AD) is a leading cause of dementia in elderly patients. The pathophysiology of AD includes various pathways, such as the degradation of acetylcholine, amyloid-beta deposition, neurofibrillary tangle formation, and neuroinflammation. Many studies showed that targeting acetylcholinesterase enzyme (AChE) to improve acetylcholine can be an effective option to treat AD. In the current work, we employed a 3D QSAR-based approach to generate a pharmacophore to screen a chemical library of compounds that may inhibit AChE. Data from experimental studies were collected and used for the generation of pharmacophores. More than 1 million compounds were screened, and further drug-like properties were determined via in-silico ADMET studies. Techniques like molecular docking and molecular dynamics simulation were performed to analyze the binding of novel AChE inhibitors. A novel AChE inhibitor ligand-1 was identified as best with a docking score of -13.560 kcal/mol with RMSD of 1.71 Å during a 100 ns MD run. Further biological studies can give an insight into the potential of ligand-1 as a therapeutic agent for AD.

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Availability of data and materials

Supplementary information (SI) is available for all relevant data free of charge via the Internet at https://doi.org/10.1007/s40203-024-00189-1.

Abbreviations

AD:

Alzheimer’s disease

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

ADMET:

Absorption, distribution, metabolism, excretion and toxicity

CAS:

Catalytic active site

HBA:

Hydrogen bond acceptor

HY:

Hydrophobic

MD:

Molecular dynamics

PAS:

Peripheral anionic site

POS:

PosIonizable: Positive ionisable

RA:

Ring aromatic

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuations

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Authors and Affiliations

  1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli, New Transit Campus, Near CRPF Base Camp, Bijnor-Sisendi Road, Sarojini Nagar, Lucknow, Uttar Pradesh, 226002, India

    Hitesh Kumar & Gopal L. Khatik

  2. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, Uttar Pradesh, 226002, India

    Ashok Kumar Datusalia

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  1. Hitesh Kumar
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Contributions

HK carried out the research work by collecting the data and performing the computational studies. AKD interpreted the results, review of the manuscript. GLK hypothesized the concept and wrote and revised the manuscript. All the authors have read and approved the final version of the manuscript.

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Correspondence to Gopal L. Khatik.

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Kumar, H., Datusalia, A.K. & Khatik, G.L. Virtual screening of acetylcholinesterase inhibitors through pharmacophore-based 3D-QSAR modeling, ADMET, molecular docking, and MD simulation studies. In Silico Pharmacol. 12, 13 (2024). https://doi.org/10.1007/s40203-024-00189-1

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