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Harnessing computational tools for drug discovery: An integrated computational approach to identify potential BACE-1 inhibitors
Journal article   Peer reviewed

Harnessing computational tools for drug discovery: An integrated computational approach to identify potential BACE-1 inhibitors

Usman Shareef, Muhammad Kazim Zargaham, Ahsan Ibrahim, Aisha Altaf and Rohail Bhatti
Journal of molecular graphics & modelling, v 139, 109076
01 Sep 2025
DOI: https://doi.org/10.1016/j.jmgm.2025.109076
PMID: 40373679
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

ADMET BACE-1 MD simulations Molecular docking Pharmacophore modeling Virtual screening
The hallmark of Alzheimer's disease (AD), a progressive neurodegenerative condition, is the buildup of amyloid-beta (Aβ) plaque, which is mainly caused by β-secretase 1 (BACE-1) activity. BACE-1 inhibition is a potentially effective treatment strategy to lower the progression of AD. In order to find possible BACE-1 inhibitors using a drug repurposing technique, this study uses an integrated computational approach that includes pharmacophore modelling, virtual screening, molecular docking, MM-GBSA, molecular dynamics (MD) simulations, in-silico ADMET profiling, and PBPK modelling. A pharmacophore model, was created with known BACE-1 inhibitors to enable virtual screening of both novel and FDA-approved chemical libraries. Top candidates with good free energy scores and strong binding affinities were found using molecular docking and MM-GBSA calculations. The stability of shortlisted Hits inside the BACE-1 active site was further validated using MD simulations, which showed that some of the important interactions were maintained across a period of 50ns. ADMET and PBPK studies predicted favorable pharmacokinetic and safety profiles for the shortlisted hits, particularly for B2 and B9. These findings identify potential candidates for future experimental validation, offering an inexpensive approach for identification of compounds as potential BACE-1 inhibitors. [Display omitted] •Alzheimer's disease most commonly affects people over the age of 65.•BACE-1 has Asp32 and Asp228 as important active site residues•Pharmacophore based virtual screening offers a cost-effective alternative to drug discovery process.•Integrated in-silico approaches are cost-effective and highly beneficial.•Pharmacophore modelling technique has emerged successful previously.

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Collaboration types
International collaboration
Web of Science research areas
Biochemical Research Methods
Biochemistry & Molecular Biology
Computer Science, Interdisciplinary Applications
Crystallography
Mathematical & Computational Biology
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