Computational Evaluation of Oleuropein Interactions with Alzheimer&#39;s Disease-Related Proteins Using Molecular Docking and Molecular Dynamics

Ahmed Elshekh; Ahmed M. Abdelmaguid; Rasha M. A. Eltanany; Youssef H. El-kordy; Asmaa A. khedr; Sara A. Mekkawy; Manal F. El-Khadragy; Ashraf Albrakati; Mohamed S. Abdelfattah; Ahmed E. Abdel Moneim

doi:10.3791/71430

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Research Article

Computational Evaluation of Oleuropein Interactions with Alzheimer's Disease-Related Proteins Using Molecular Docking and Molecular Dynamics

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DOI:

10.3791/71430

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June 30th, 2026

Ahmed Elshekh^*¹ , Ahmed M. Abdelmaguid^*¹ , Rasha M. A. Eltanany¹ , Youssef H. El-kordy² , Asmaa A. khedr² , Sara A. Mekkawy¹ , Manal F. El-Khadragy³ , Ashraf Albrakati^*⁴ , Mohamed S. Abdelfattah¹ , Ahmed E. Abdel Moneim⁵

¹Chemistry Department, Faculty of Science, Capital University, ²Department of Zoology, Faculty of Science, Capital University, ³Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, ⁴Department of Human Anatomy, College of Medicine, Taif University, ⁵Unit of Scientific Research, Applied College, Qassim University

^* These authors contributed equally

Summary

This study presents an integrated molecular docking and molecular dynamics workflow to computationally evaluate the interactions of oleuropein with key Alzheimer’s disease-related proteins, revealing predicted binding interactions and preliminary complex stability across multiple targets.

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder associated with amyloid aggregation, tau pathology, and neuroinflammation. In this study, an integrated computational workflow combining ADMET prediction, PASS-based activity screening, molecular docking, and molecular dynamics (MD) simulations was employed to evaluate the interactions of oleuropein with five AD-related protein targets, including β-amyloid, tau, apolipoprotein E4 (ApoE4), triggering receptor expressed on myeloid cells 2 (TREM2), and complement protein C1q. ADMET and PASS analyses predicted pharmacokinetic properties and potential biological activities associated with neurodegenerative disease-related pathways. Docking analysis predicted favorable binding affinities across the investigated targets, with the strongest predicted interaction observed for the C1q protein (-7.5 kcal/mol). Molecular dynamics (MD) trajectory analyses, including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), dynamic cross-correlation matrix (DCCM), principal component analysis (PCA), and distance-based metrics, were used to evaluate the dynamic behavior of the protein-ligand complexes during the simulations. The computational analyses suggested relatively stable interactions for tau, C1q, and TREM2 complexes, whereas β-amyloid and ApoE4 exhibited comparatively higher conformational variability during portions of the simulations. These findings provide a preliminary computational assessment of oleuropein interactions with AD-related proteins and may support future experimental studies investigating its potential biological relevance in neurodegenerative disease models.

Introduction

AD represents the most common type of dementia that generates serious and escalating challenges worldwide¹^,². AD arises from a combination of genetic and environmental factors. Multiple pathogenic hypotheses have been proposed to explain AD, including cholinergic, amyloid, tau, inflammatory, oxidative stress, metal ion, excitotoxicity, microbiota-gut-brain axis, and autophagy-related mechanisms³. AD is a multifactorial disorder involving β-amyloid deposition, tau pathology, neuroinflammation, and genetic risk factors such as ApoE4 and TREM2⁴^,