Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

Zagórska, Agnieszka; Jaromin, Anna

doi:10.3390/molecules25153337

Cited by 51Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesComputational Drug Discovery Methods

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

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Zagórska, Agnieszka, Jaromin, Anna·2020·Molecules

DOI 10.3390/molecules25153337PMC PMC7435667

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Abstract

Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.

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Cholinergic dysfunction was the first hypothesis postulated and is considered one of the most relevant causes of Alzheimer's disease.
“Cholinergic dysfunction was the first hypothesis postulated and is considered one of the most relevant causes of AD.”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [17]
Almost all pharmacological options currently in therapy for Alzheimer's disease are aimed at strengthening the cholinergic system through inhibition of acetylcholinesterase/butyrylcholinesterase enzymatic function.
“almost all the pharmacological options currently in therapy are aimed at strengthening the cholinergic system through the inhibition of the AChE/BuChE enzymatic function [17].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [17]
There are five drugs in clinic for Alzheimer's disease, including three cholinesterase inhibitors, that only provide palliative and supporting treatment.
“There are five drugs in clinic, including three cholinesterase inhibitors, that only provide palliative and supporting treatment (Butterfield and Boyd-Kimball, 2020;Zagórska and Jaromin, 2020;Gul et al., 2021).”
From Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease (2022) · cites this paper as Zagórska and Jaromin, 2020
There is still a lack of effective drugs for the treatment of Alzheimer's disease.
“Despite incredible efforts, there is still a lack of effective drugs for the treatment of AD.”
From Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease (2022) · cites this paper as Zagórska and Jaromin, 2020
ChE inhibitors are not able to completely stop the progression of AD.
“However, ChE inhibitors are not able to completely stop the progression of AD, and research should focus on the development of multi-target drugs able to counteract the decreased levels of ACh, protein misfolding and associated Aβ aggregation, hyperphosphorylation of tau protein, and oxidative stress (Butterfield and Boyd-Kimball, 2020;Zagórska and Jaromin, 2020).”
From Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease (2022) · cites this paper as Zagórska and Jaromin, 2020

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[208]Moore Z. Taylor J.M. Crack P.J. The involvement of microglia in Alzheimer’s disease: A new dog in the fight Br. J. Pharmacol. 2019 176 3533 3543 10.1111/bph.14546 30445661 PMC6715787 · DOI · Paper page

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Authors: Zagórska, A., & Jaromin, A.
Affiliations: Jagiellonian University (PL)
University of Wrocław (PL)
Corresponding author: Zagórska, Agnieszka
ORCID: Zagórska, Agnieszka
Jaromin, Anna
Venue: Molecules
Publisher: MDPI AG
Published: 2020-07-23
Volume: 25
Issue: 15
Pages: 3337
ISSN: 1420-3049 (ISSN-L)
DOI: 10.3390/molecules25153337
PMC: PMC7435667
OpenAlex: W3044136434
Cited by: 51
References: 222
Citations by year: 2026: 5 · 2025: 8 · 2024: 8 · 2023: 10 · 2022: 10 · 2021: 9 · 2020: 1
FWCI: 0.95
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Molecules (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Uniwersytet Jagielloński w Krakowie (06/IDUB/2019/94)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords: Alzheimer's disease, multi-target drugs, polypharmacology, acetylcholinesterase, BACE1, GSK3β, NMDA receptor, monoamine oxidase, serotonin receptors, histamine H3 receptor, phosphodiesterase, microglia, therapeutic target, Alzheimer's disease treatment
MeSH terms: Glycogen Synthase Kinase 3 beta, Acetylcholinesterase, Alzheimer Disease, Clinical Trials as Topic, Enzyme Inhibitors, Humans, Ligands, Monoamine Oxidase, Phosphoric Diester Hydrolases, Receptors, Serotonin, Molecular Structure, Receptors, N-Methyl-D-Aspartate, Aspartic Acid Endopeptidases, Receptors, Histamine H3, Amyloid Precursor Protein Secretases, GPI-Linked Proteins, Polypharmacology

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Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

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