Multitarget Drug Design Strategy in Alzheimer'S Disease: Focus on Cholinergic Transmission and Amyloid-β Aggregation

Simoni, Elena; Bartolini, Manuela; Abu, Izuddin Fahmy; Blockley, Alix; Gotti, Cecilia; Bottegoni, Giovanni; Caporaso, Roberta; Bergamini, Christian; Andrisano, Vincenza; Cavalli, Andrea; Mellor, Ian R.; Minarini, Anna; Rosini, Michela

doi:10.4155/fmc-2017-0039

Cited by 19 publications

(5 citation statements)

References 47 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, excessive synthesis of ACHE may indirectly lead to the formation of amyloid, which adversely affects the brain. To date, anti-AChE is still the first-line drug used to reduce the symptoms of AD [47,48].…”

Section: Excess Synthesis Of Achementioning

confidence: 99%

Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions

Hong

Yang

2022

Molecules

View full text Add to dashboard Cite

The amyloid hypothesis of Alzheimer’s disease has long been the predominant theory, suggesting that Alzheimer’s disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer’s disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain.

show abstract

Section: Excess Synthesis Of Achementioning

confidence: 99%

Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions

Hong

Yang

2022

Molecules

View full text Add to dashboard Cite

show abstract

“…Following a ligand-based approach, hybrid compounds addressing both systems were synthetized and subsequently pharmacologically studied. The molecules combine an α 7 agonist and a carbazole moiety having AChE inhibition properties (( 49a,b ), Figure 26) [125]. Substituted carbazoles are able to interact with the narrow inner part of the AChE enzyme gorge and also present anti-amyloidogenic activity.…”

Section: Nicotinic Receptormentioning

confidence: 99%

Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease

Volpato

Holzgrabe

2018

Molecules

View full text Add to dashboard Cite

The cholinergic hypothesis has been reported first being the cause of memory dysfunction in the Alzheimer’s disease. Researchers around the globe have focused their attention on understanding the mechanisms of how this complicated system contributes to processes such as learning, memory, disorientation, linguistic problems, and behavioral issues in the indicated chronic neurodegenerative disease. The present review reports recent updates in hybrid molecule design as a strategy for selectively addressing multiple target proteins involved in Alzheimer’s disease (AD) and the study of their therapeutic relevance. The rationale and the design of the bifunctional compounds will be discussed in order to understand their potential as tools to investigate the role of the cholinergic system in AD.

show abstract

“…Multifunctionality has become the new paradigm in the design of drugs aimed to treat multifactorial diseases [ 77 , 78 ], including neurodegenerative disorders [ 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ]. Some of the advantages of these drugs, over drug-cocktails or coformulations, are: (i) Simplified therapeutic regimes, (ii) reduced risks of drug interactions, (iii) less complex pharmacodynamics and pharmacokinetics, (iv) additive, or synergistic, therapeutic responses, and (v) no increased side effects [ 64 , 77 , 78 , 95 ].…”

Section: Introductionmentioning

confidence: 99%

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants

Guzmán‐López

Reina²,

Pérez-González³

et al. 2022

IJMS

View full text Add to dashboard Cite

A computational protocol aimed to design new antioxidants with versatile behavior is presented. It is called Computer-Assisted Design of Multifunctional Antioxidants and is based on chemical properties (CADMA-Chem). The desired multi-functionality consists of in different methods of antioxidant protection combined with neuroprotection, although the protocol can also be used to pursue other health benefits. The dM38 melatonin derivative is used as a study case to illustrate the protocol in detail. This was found to be a highly promising candidate for the treatment of neurodegeneration, in particular Parkinson’s and Alzheimer’s diseases. This also has the desired properties of an oral-drug, which is significantly better than Trolox for scavenging free radicals, and has chelates redox metals, prevents the ●OH production, via Fenton-like reactions, repairs oxidative damage in biomolecules (lipids, proteins, and DNA), and acts as a polygenic neuroprotector by inhibiting catechol-O-methyl transferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase B (MAOB). To the best of our best knowledge, CADMA-Chem is currently the only protocol that simultaneously involves the analyses of drug-like behavior, toxicity, manufacturability, versatile antioxidant protection, and receptor–ligand binding affinities. It is expected to provide a starting point that helps to accelerate the discovery of oral drugs with the potential to prevent, or slow down, multifactorial human health disorders.

show abstract

Multitarget Drug Design Strategy in Alzheimer'S Disease: Focus on Cholinergic Transmission and Amyloid-β Aggregation

Abstract: The compounds emerged as a suitable starting point for a further optimization process.

Cited by 19 publications

References 47 publications

Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions

Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions

Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants

Contact Info

Product

Resources

About