In silico identification of AChE and PARP-1 dual-targeted inhibitors of Alzheimer’s disease

Hu, Xingjian; Wang, Dong; Cui, Zhiwen; Gao, Chengzhi; Yu, Zhijun; Yuan, Qiong; Zhou, Min

doi:10.1007/s00894-018-3696-6

Cited by 15 publications

(3 citation statements)

References 42 publications

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“…In the light of the multifactorially pathological mechanisms of AD, developing multitarget-directed ligands (MTDLs) may be a more promising approach for its treatment. Some researches and reviews of MTDLs for AD have already been reported 18 , 19 , but almost none of which is related to both PARP-1 and cholinesterase inhibitors 20 . In this regard, the PARP-1 and cholinesterase dual-targeted inhibitor of AD are worthy to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Gao

Wang

Cui

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Gao

Wang

Cui

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…When there is AD pathology present, activated PARP-1 encourages NF-kB to attach to DNA in microglia. Parallel to this, a number of studies have shown that inhibiting PARP-1 can halt the development of AD 91 92 93 94 . In mice lacking PARP-1, Aβ-induced microglial activation is reduced.…”

Section: Introductionmentioning

confidence: 92%

A Review of PARP-1 Inhibitors: Assessing Emerging Prospects and Tailoring Therapeutic Strategies

Ramesh,

Almeida,

Hammigi

et al. 2023

Drug Res (Stuttg)

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Eukaryotic organisms contain an enzyme family called poly (ADP-ribose) polymerases (PARPs), which is responsible for the poly (ADP-ribosylation) of DNA-binding proteins. PARPs are members of the cell signaling enzyme class. PARP-1, the most common isoform of the PARP family, is responsible for more than 90% of the tasks carried out by the PARP family as a whole. A superfamily consisting of 18 PARPs has been found. In order to synthesize polymers of ADP-ribose (PAR) and nicotinamide, the DNA damage nick monitor PARP-1 requires NAD+ as a substrate. The capability of PARP-1 activation to boost the transcription of proinflammatory genes, its ability to deplete cellular energy pools, which leads to cell malfunction and necrosis, and its involvement as a component in the process of DNA repair are the three consequences of PARP-1 activation that are of particular significance in the process of developing new drugs. As a result, the pharmacological reduction of PARP-1 may result in an increase in the cytotoxicity toward cancer cells.

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“…In the presence of AD pathology, activated PARP1 promotes the DNA binding of NF‐κB in microglia [63]. Similarly, a cluster of data has confirmed that PARP1 inhibition could delay the progression of AD [64,65]. Aβ‐induced microglial activation is mitigated in mice deficient for Parp1 [66].…”

Section: Parp1 and Alzheimer's Diseasementioning

confidence: 99%

The role of PARP1 in neurodegenerative diseases and aging

Mao

Zhang

2021

The FEBS Journal

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Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive memory loss and motor impairment. Aging is a major risk factor for neurodegenerative diseases. Neurodegenerative diseases and aging often develop in an irreversible manner and cause a significant socioeconomic burden. When considering their pathogenesis, many studies usually focus on mitochondrial dysfunction and DNA damage. More recently, neuroinflammation, autophagy dysregulation, and SIRT1 inactivation were shown to be involved in the pathogenesis of neurodegenerative diseases and aging. In addition, studies uncovered the role of poly (ADP-ribose)-polymerase-1 (PARP1) in neurodegenerative diseases and aging. PARP1 links to a cluster of stress signals, including those originated by inflammation and autophagy dysregulation. In this review, we summarized the recent research progresses on PARP1 in neurodegenerative diseases and aging, with an emphasis on the relationship among PARP1, neuroinflammation, mitochondria, and autophagy. We discussed the possibilities of treating neurodegenerative diseases and aging through targeting PARP1.

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In silico identification of AChE and PARP-1 dual-targeted inhibitors of Alzheimer’s disease

Cited by 15 publications

References 42 publications

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

A Review of PARP-1 Inhibitors: Assessing Emerging Prospects and Tailoring Therapeutic Strategies

The role of PARP1 in neurodegenerative diseases and aging

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