Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation

Sunil Kumar; Amritha Manoharan; Jayalakshmi J; Mohamed A. Abdelgawad; Wael A. Mahdi; Sultan Alshehri; Mohammed M. Ghoneim; Leena K. Pappachen; Subin Mary Zachariah; T. P. Aneesh; Bijo Mathew

doi:10.1039/D3RA00526G

Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation†

Sunil Kumar,^a Amritha Manoharan,^a Jayalakshmi J,^a Mohamed A. Abdelgawad,^bc Wael A. Mahdi,^d Sultan Alshehri,

^d Mohammed M. Ghoneim,^ef Leena K. Pappachen,^a Subin Mary Zachariah,^a T. P. Aneesh*^a and Bijo Mathew

*^a

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* Corresponding authors

^a Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, India

^b Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
E-mail: bijomathew@aims.amrita.edu, bijovilaventgu@gmail.com, aneeshtp@aims.amrita.edu

^c Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt

^d Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

^e Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, Saudi Arabia

^f Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

Abstract

Alzheimer's disease (AD), a neurodegenerative condition associated with ageing, can occur. AD gradually impairs memory and cognitive function, which leads to abnormal behavior, incapacity, and reliance. By 2050, there will likely be 100 million cases of AD in the world's population. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition are significant components of AD treatment. This work developed models using the genetic method multiple linear regression, atom-based, field-based, and 3-D pharmacophore modelling. Due to internal and external validation, all of the models have solid statistical (R² > 0.81 and Q² > 0.77) underpinnings. From a pre-plated CNS library (6055), we discovered a hit compound using virtual screening on a QSAR model. Through molecular docking, additional hit compounds were investigated (XP mode). Finally, a molecular dynamics simulation revealed that the Molecule5093-4BDS complex was stable (100 ns). Finally, the expected ADME properties for the hit compounds (Molecule5093, Molecule1076, Molecule4412, Molecule1053, and Molecule3344) were found. According to the results of our investigation and the prospective hit compounds, BuChE inhibitors may be used as a treatment for AD.

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Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation†

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Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation

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