Novel GSK-3β inhibitors from sequential virtual screening

Kim, Hye Jung; Choo, Hyunah; Cho, Yong Seo; No, Kyoung Tai; Pae, Ae Nim

doi:10.1016/j.bmc.2007.10.047

Cited by 46 publications

(31 citation statements)

References 21 publications

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“…Based on the chemical structure of the GSK3β inhibitors 1 37 and 2 38 (Fig. 1), we thought that compounds bearing the 1,4-dihydropyridine core or the isostere 4 H -pyran could be suitable as GSK3β inhibitors and we searched for their potential Nrf2 induction.…”

Section: Resultsmentioning

confidence: 99%

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Gameiro

Michalska

Tenti

et al. 2017

Sci Rep

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The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.

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Section: Resultsmentioning

confidence: 99%

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Gameiro

Michalska

Tenti

et al. 2017

Sci Rep

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“…[63, 66] They bind to targets as diverse as G-Protein-coupled receptor 40 (GPR40), [67] protein tyrosine phosphatase 3 (PRL-3), [68] cyclooxygenase 2 (COX-2), [69] MurB, C & G, [63] B-cell lymphoma-2 (Bcl-2), [70] phosphodiesterase 4 (PDE4), [71] fungal protein mannosyl transferase 1 (PMT1), [72] tumour necrosis factor alpha (TNF-α), [73] Hepatitis C virus nonstructural protein 3 (HCV NS3) and NS5b polymerase (HCV NS5b), [74, 75] cytosolic phospholipase A2α (cPLA2α), [76] proto-oncogene serine/threonine-protein kinase (Pim-1), [77] cyclin-dependent kinase 2 (CDK2), [54] HIV-1 integrase, [78] serotonin N-acetyltransferase (AANAT) [79] and glycogen synthase kinase-3β (GSK-3β). [80] Several of the most potent compounds identified here have also been picked up in other screening campaigns, offering a cautionary note to the possibility of off-target effects. Frequent reporting in their identification via screening may be due to the low IC50 activity assigned for a “hit” which is often ~ 25 µM, representing only weak affinity for the target of interest.…”

Section: Resultsmentioning

confidence: 99%

Thiazolidinedione‐Based PI3Kα Inhibitors: An Analysis of Biochemical and Virtual Screening Methods

Pinson¹,

Schmidt‐Kittler

Zhu

et al. 2011

ChemMedChem

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A series of synthesized and commercially available compounds were assessed against PI3Kα for in vitro inhibitory activity and the results compared to binding calculated in silico. Using published crystal structures of PI3Kγ and PI3Kδ co-crystallized with inhibitors as a template, docking was able to identify the majority of potent inhibitors from a decoy set of 1000 compounds. On the other hand, PI3Kα as the apo-form or modelled by induced fit docking or built as a homology model gave only poor results. A PI3Kα homology model derived from a liganded PI3Kδ crystal structure was developed which has good ability to identify active compounds. The docking results identified binding poses for active compounds that differ from those identified to date and can contribute to our understanding of structure-activity relationships for PI3K inhibitors.

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“…Even though the binding mode of the compounds in Table 6 is likely to be the one (binding mode 1) described above, we decided to investigate other possible binding modes, especially in light of the fact that a different binding conformation was previously proposed 19,24,56. First, we examined the relative conformational energy of different possible binding conformations of an unsubstituted 3-(benzofuran-3-yl)-4-(indol-3-yl)maleimide to the GSK-3β binding pocket.…”

Section: Resultsmentioning

confidence: 99%

Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3β inhibitors

et al. 2009

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Molecular modelling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies have been used to determine the correct binding mode of glycogen synthase kinase 3β (GSK-3β) inhibitors. The approaches of Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) are used for the 3D-QSAR of 51 substituted 3-benzofuranyl-4-indolyl-maleimides as GSK-3β inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3β are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined pIC 50 values has the following statistics: R 2 (cv) = 0.386 and SE(cv) = 0.854 for the cross-validation, and R 2 = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and Probability.of R 2 = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of X-ray crystal structures of inhibitor-bound GSK-3β. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds.

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Novel GSK-3β inhibitors from sequential virtual screening

Cited by 46 publications

References 21 publications

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Thiazolidinedione‐Based PI3Kα Inhibitors: An Analysis of Biochemical and Virtual Screening Methods

Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3β inhibitors

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