Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3

Sciú, María L.; Sebastián-Pérez, Víctor; Martínez-González, Loreto; Benı́tez, Rocı́o; Pérez, Daniel I.; Pérez, Concepción; Campillo, Nuria E.; Martı́nez, Ana; Moyano, Elizabeth L.

doi:10.1080/14756366.2018.1530223

Cited by 12 publications

(6 citation statements)

References 39 publications

(37 reference statements)

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“…MD simulation could provide valuable information to understand the dynamic properties of protein–ligand interactions [ 26 ]. In this study, we selected the optimal binding conformation for 90 ns MD simulation to observe the interaction between GluA1 and CGA and structural stability of the complex on the time scale.…”

Section: Resultsmentioning

confidence: 99%

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Zhu

et al. 2022

Molecules

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Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 μM). The SPR assay demonstrates that CGA can directly bind to GluA1 (KD = 496 μM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is −39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1–CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future.

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Section: Resultsmentioning

confidence: 99%

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Zhu

et al. 2022

Molecules

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“…Pyrazolotriazines were identified as biologically active compounds with inhibitory activity towards histone deacetylases [ 9 ], metalloproteinases [ 10 ], tubulin [ 11 ], urease and tyrosinase [ 12 , 13 ]. Moreover, some of them inhibit protein kinases engaged in pivotal signaling pathways driving cancer cell proliferation, including ABL kinase [ 14 , 15 ], cyclin-dependent kinases (CDKs) [ 16 , 17 ], casein kinase 2 (CK2) [ 18 , 19 ], and glycogen synthase kinase 3 (GSK3) [ 20 ]. The addition of the sulfonamide moiety to the pyrazolotriazine scaffold allowed for the broadening of the array of possible molecular targets of these compounds [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Preparation of Novel Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides and Their Experimental and Computational Biological Studies

Kciuk

Mujwar

Szymanowska

et al. 2022

IJMS

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Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides constitute a novel class of heterocyclic compounds with broad biological activity, including anticancer properties. Investigated in this study, MM-compounds (MM134, MM136, MM137, and MM139) exhibited cytotoxic and proapoptotic activity against cancer cell lines (BxPC-3, PC-3, and HCT-116) in nanomolar concentrations without causing cytotoxicity in normal cells (L929 and WI38). In silico predictions indicate that tested compounds exhibit favorable pharmacokinetic profiles and may exert anticancer activity through the inhibition of BTK kinase, the AKT-mTOR pathway and PD1-PD-L1 interaction. Our findings point out that these sulfonamide derivatives may constitute a source of new anticancer drugs after optimization.

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“…An in-vitro model was used to assess tau hyperphosphorylation in cells. It can be considered new leads for more optimization in the area of AD pharmacotherapy 60 . Tideglusib (Table 3) is a GSK-3β non-ATP competitive inhibitor.…”

Section: Non-atp Competitive Inhibitionmentioning

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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Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3

Cited by 12 publications

References 39 publications

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Preparation of Novel Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides and Their Experimental and Computational Biological Studies

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

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