Targeting GluR3 in Depression and Alzheimer’s Disease: Novel Compounds and Therapeutic Prospects

Article type: Research Article

Authors: Saeed, Amir^{a; b; 1; *} | Alharazi, Talal^{a; 1} | Alshaghdali, Khalid^a | Rezgui, Raja^a | Elnaem, Ibtihag^c | Alreshidi, Bunder Albdullah T.^d | Tasleem, Munazzah^e | Saeed, Mohd^f

Affiliations: [a] Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia | [b] Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Medical Sciences & Technology, Khartoum, Sudan | [c] Department of oral and maxillofacial surgery and diagnostic science College of Dentistry, University of Hail, Hail, Saudi Arabia | [d] Blood Bank Department, Hail General Hospital, Hail, Saudi Arabia | [e] School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, Sichuan, China | [f] Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia

Correspondence: [*] Correspondence to: Amir Saeed, Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:The present study investigates the interrelated pathophysiology of depression and Alzheimer’s disease (AD), with the objective of elucidating common underlying mechanisms. Objective:Our objective is to identify previously undiscovered biogenic compounds from the NuBBE database that specifically interact with GluR3. This study examines the bidirectional association between depression and AD, specifically focusing on the role of depression as a risk factor in the onset and progression of the disease. Methods:In this study, we utilize pharmacokinetics, homology modeling, and molecular docking-based virtual screening techniques to examine the GluR3 AMPA receptor subunit. Results:The compounds, namely ZINC000002558953, ZINC000001228056, ZINC000000187911, ZINC000003954487, and ZINC000002040988, exhibited favorable pharmacokinetic profiles and drug-like characteristics, displaying high binding affinities to the GluR3 binding pocket. Conclusions:These findings suggest that targeting GluR3 could hold promise for the development of therapies for depression and AD. Further validation through in vitro, in vivo, and clinical studies is necessary to explore the potential of these compounds as lead candidates for potent and selective GluR3 inhibitors. The shared molecular mechanisms between depression and AD provide an opportunity for novel treatment approaches that address both conditions simultaneously.

Keywords: ADMET, Alzheimer’s disease, GluR3, homology modeling, major depressive disorder, molecular docking, NuBBE_DB

DOI: 10.3233/JAD-230821

Journal: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1299-1312, 2024