Multi-target-directed-ligands acting as enzyme inhibitors and receptor ligands

Rodríguez-Soacha, Diego Alejandro; Scheiner, Matthias; Decker, Michael

doi:10.1016/j.ejmech.2019.07.040

Cited by 30 publications

(19 citation statements)

References 205 publications

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“…[8] This positive effect has already been demonstrated with the use of RS67333 a reference 5-HT 4 R agonist, in primary neurons, [9] and led to the in vivo improvement of memory in several animal models of AD [10]. Indeed, in the context of AD, the activation of 5-HT 4 Rs with agonist has led to the increase in neurotransmitter release as well as a clear impact of amyloid load in transgenic mice models after chronic administration. Several 5-HT 4 R agonists have been studied in clinical This secondary target was chosen because of the ability of 5-HT4R agonists to favor the "non-amyloidogenic" cleavage of the amyloid precursor protein (APP) by α-secretase, inducing then a decrease in amyloid pathology.…”

Section: Introductionmentioning

confidence: 87%

“…In the field of Alzheimer’s disease (AD), multiple in vitro or in vivo MTDL candidates have been generated over the last years and could lead to preclinical or clinical opportunities [ 3 ]. Because of its validated interest in the treatment of AD symptoms, acetylcholinesterase (AChE) inhibitors, such as donepezil, have been chosen as a starting point to develop novel analogs with a second biological target such as receptors [ 4 ]. As an example, we recently described the preclinical candidate donecopride, the first MTDL able to demonstrate AChE inhibition and activating serotoninergic receptors 5-HT 4 ( Figure 1 ) [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy

et al. 2021

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The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer’s disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy

et al. 2021

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“…[76] A high throughput virtual screening and other in silico simulations have been used to develop MTDLs as a potential model to design inhibitors for both AChE and BChE which has proven to be more effective than one-target ligand approach. [77] Molecular docking and MD simulations can be used to reveal the crucial interactions between investigated ligands and amino acid residues at various regions of the active sites of AChE and BChE. Again, we used the keywords "ChE/ AChE; BChE; multi/dual inhibitor; and in silico/theoretical/ computational study" in the Web of Science and Scopus databases published within 2010 and 2020 and found 39 research articles.…”

Section: In Silico-based Identification Of Dual Inhibitors Of Ache Anmentioning

confidence: 99%

Design and Development of Cholinesterase Dual Inhibitors towards Alzheimer's Disease Treatment: A Focus on Recent Contributions from Computational and Theoretical Perspective

2020

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In recent times, review topics on Alzheimer's disease (AD) have received massive attention, especially on drug design and development of potent inhibitors targeting specific pathway(s) of this multifaceted disease. Drug design and development through the use of computer has taken an intriguing dimension over the last two decades, and AD drug design is not an exception. Computational approaches have found usage in identifying potentially active molecules targeting specific enzyme or gene in the pathological pathway of a disease such as AD. Herein, we present an overview of research contributions over the last ten years from different authors who had used computational approaches to explore potent dual inhibitors of the cholinesterase enzymes linked with AD patho-genesis. We gave an introductory background of the disease, highlight challenges of in silico approach to drug design, and discuss its pros and cons. The overview also covers previously reported review works which are related to the topic. We proposed that continued research efforts to unravel more effective dual acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors through computational tools could plausibly be a successful approach to AD cure. Computational researchers should leverage on the available cost-effective resources to identify lead compounds and work in collaboration with experimental personnel to push their discovery forward.

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“…This stems from limitations in finding common binding modes and structural features for targets with different location and structural requirements. 15 Among examples of such an approach, the dual-acting compounds described thus far include AchE inhibitors and NMDA receptor antagonists, 16 AChE and histamine H3 receptor (H3R) antagonists, 17 AChE inhibitors and sigma σ1 receptor ligands, 18 AChE inhibitors and serotonin 5-HT4R agonists 19 or AChE inhibitors and 5-HT6R antagonists. 20 Serotonin type 6 receptor (5-HT6R) is a GPCR which has emerged as a promising target for the treatment of pro-cognitive deficits of neurodegenerative and psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

Canale

Grychowska

Kurczab

et al. 2020

European Journal of Medicinal Chemistry

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The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking 5-HT6R scaffolds with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay and artificial membrane permeability, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.

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Multi-target-directed-ligands acting as enzyme inhibitors and receptor ligands

Cited by 30 publications

References 205 publications

Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy

Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy

Design and Development of Cholinesterase Dual Inhibitors towards Alzheimer's Disease Treatment: A Focus on Recent Contributions from Computational and Theoretical Perspective

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

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