Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease
Open accessAbstract
Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer’s disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies.
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Cell-based systems are a compromise between isolated proteins and in vivo screening, maintaining experimental efficiency while preserving critical molecular pathway interactions.
“From a polypharmacology perspective, the cell-based systems are a perfect compromise between isolated proteins and in vivo screening: they maintain a reasonable experimental efficiency while preserving critical molecular pathway interactions.3”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [3]
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References 62 · Cited by 110
- Authors
- Prati, F., Cavalli, A., & Bolognesi, M.
- Affiliations
- University of Dundee (GB)
- Italian Institute of Technology (IT)
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
- Corresponding author
- Cavalli, Andrea
- Venue
- Molecules
- Publisher
- MDPI AG
- Published
- 2016-04-08
- Volume
- 21
- Issue
- 4
- Pages
- 466
- ISSN
- 1420-3049 (ISSN-L)
- PMC
- PMC6273289
- OpenAlex
- W2317110841
- Cited by
- 110
- References
- 62
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 14 · 2021: 15 · 2020: 12 · 2019: 15 · 2018: 13 · 2017: 12 · 2016: 3
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecules (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca (20103W4779)
- Università di Bologna
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- multi-target-directed ligands, Alzheimer's disease, hybrid molecules, fragment-based drug discovery, acetylcholinesterase inhibitors, NMDA receptor antagonists, metal chelation, BACE1 inhibitors, GSK-3β inhibitors, rational drug design, drug-likeness
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Acetylcholinesterase, Alzheimer Disease, Cholinesterase Inhibitors, Humans, Ligands, Receptors, N-Methyl-D-Aspartate, Aspartic Acid Endopeptidases, Amyloid Precursor Protein Secretases, Drug Discovery
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