Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

Silva, Guilherme Martins; Barcelos, Mariana Pegrucci; Poiani, João Gabriel Curtolo; Hage‐Melim, Lorane Izabel da Silva; Silva, Carlos Henrique Tomich de Paula da

doi:10.1002/cmdc.201900299

Cited by 4 publications

(5 citation statements)

References 232 publications

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“… Tang et al, 2020 ; Mony et al, 2009 ; Costa et al, 2010 ; Perszyk et al, 2018 ; Warikoo et al, 2018 ). Moreover, none are FDA-approved ( Wilkinson and Sanacora, 2019 ; Silva et al, 2019 ). A recent report suggests an alternative approach consisting of the use of L-serine for enhancing channel activity ( Soto et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy

Kellner

Abbasi

Carmi

et al. 2021

eLife

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The N-methyl-D-aspartate receptors (NMDARs; GluNRS) are glutamate receptors, commonly located at excitatory synapses. Mutations affecting receptor function often lead to devastating neurodevelopmental disorders. We have identified two toddlers with different heterozygous missense mutations of the same, and highly conserved, glycine residue located in the ligand-binding-domain of GRIN2B: G689C and G689S. Structure simulations suggest severely impaired glutamate binding which we confirm by functional analysis. Both variants show three-orders of magnitude reductions in glutamate EC50, with G689S exhibiting the largest reductions observed in GRIN2B (~2000-fold). Moreover, variants multimerize with, and upregulate, GluN2Bwt-subunits, thus engendering a strong dominant-negative effect on mixed channels. In neurons, overexpression of the variants instigates suppression of synaptic GluNRs. Lastly, while exploring spermine potentiation as a potential treatment, we discovered that the variants fail to respond due to G689's novel role in proton-sensing. Together, we describe two unique variants with extreme effects on channel function. We employ protein-stability measures to explain why current (and future) LBD mutations in GluN2B primarily instigate Loss-of-Function.

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Section: Introductionmentioning

confidence: 99%

Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy

Kellner

Abbasi

Carmi

et al. 2021

eLife

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“…These GSK-3β allosteric inhibitors are still being studied, to optimize their drug-like properties and design new compounds based on their scaffolds. It's worth noting that their paper is very useful in identifying the certain potential site of allosteric on the enzyme's topography, which is one of the most critical current targets in the context of AD 64 .…”

Section: Allosteric Inhibitorsmentioning

confidence: 99%

Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease

Shri¹,

Manandhar²,

Nayak³

et al. 2023

Adv Pharm Bull

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Glycogen synthase Kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wide variety of biological processes, including early embryo formation, oncogenesis, as well cell death in neurodegenerative diseases. Several critical cellular processes in the brain are regulated by the GSK-3β, serving as a central switch in the signalling pathways. Dysregulation of GSK-3β kinase has been reported in cancer, diabetes, Alzheimer's disease, schizophrenia, bipolar disorder, inflammation, and Huntington's disease. Thus, GSK-3β is widely regarded as a promising target for therapeutic use. The current review article focuses mainly on Alzheimer's disease, an age-related neurodegenerative brain disorder. GSK-3β activation increases amyloid-beta (Aβ) and the development of neurofibrillary tangles that are involved in the disruption of material transport between axons and dendrites. The drug-binding cavities of GSK-3β are explored, and different existing classes of GSK-3β inhibitors are explained in this review. Non-ATP competitive inhibitors, such as allosteric inhibitors, can reduce the side effects compared to ATP-competitive inhibitors. Whereas ATP-competitive inhibitors produces disarrangement of the cytoskeleton, neurofibrillary tangles formation, and leads to the death of neurons, etc. This could be because they are binding to a site separate from ATP. Owing to their interaction in particular and special binding sites, allosteric ligands interact with substrates more selectively, which will be beneficial in resolving drug-induced resistance and also helpful in reducing side effects. Hence, in this review, we focussed on the allosteric GSK-3β inhibitors and discussed their futuristic opportunities as anti-Alzheimer’s drug.

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“…Also commonly reported is the class of GSK-3β inhibitors known as ATP competitive inhibitors, which compete for the same site as ATP in the enzyme’s orthosteric cavity, and from which compounds with considerable bioactivity are known (such as indirubin and hymeldiasine, among others) [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Non-ATP competitive inhibitors—which generally include substrate-competitive and allosteric inhibitors—have been studied as an alternative to ATP-competitive inhibitors since they potentially cause fewer side effects, despite presenting lower potency/affinity towards GSK-3β. Within this class, we can highlight tideglusib, which inhibits GSK-3β irreversibly but does not block the whole pool of enzymes within cells; it has reached phase II clinical trials [ 19 , 20 ]. Nevertheless, commonly and unfortunately, there is no further elucidation on how (and by which mechanism) non-ATP-competitive compounds exert inhibition, and there is also a lack of information concerning which cavities (or pockets) of GSK-3β they act on.…”

Section: Introductionmentioning

confidence: 99%

“…According to Silva et al [ 19 ], there are few classes of GSK-3β allosteric inhibitors discovered so far, and there are still some peculiarities of respective mechanisms to be unveiled. For instance, palinurin, a compound found in marine organisms, was revealed as a new class of GSK-3β allosteric inhibitors, with IC 50 = 1.9 μM, along with suggestions that it should bind to allosteric Pocket 5 (from Figure 1 ) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases

Silva

Borges

Santos

et al. 2021

IJMS

Self Cite

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Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3β allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3β allosteric modulators.

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Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

Cited by 4 publications

References 232 publications

Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy

Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy

Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease

Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases

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