Probing the physicochemical and structural requirements for glycogen synthase kinase-3α inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides

Sivaprakasam, Prasanna; Xie, Aihua; Doerksen, Robert J.

doi:10.1016/j.bmc.2006.09.021

Cited by 38 publications

(32 citation statements)

References 47 publications

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“…Two green polyhedra around the ortho and meta positions of the 4-phenyl ring suggest that bulky substituents at these positions will increase GSK-3a inhibitory activity. This confirms our Hansch 2D-QSAR findings that ortho steric descriptors r, f, and E s for the 4-phenyl ring (where r = Hammett electronic substituent constant, f = inductive parameter and E s = steric descriptor), are positively correlated to activity [22]. The other big green region surrounding the meta and para positions of the 3-anilino ring shows that bulky groups in these positions enhance activity.…”

Section: Model Statisticssupporting

confidence: 82%

“…Previously we published a 2D-QSAR analysis using classical Hansch [29] and Fujita-Ban methods for 67 of the 74 Smith et al maleimides, including 3-anilino and 3-N-methylanilinomaleimides [22]. Some 3D-QSAR and other molecular modeling studies have been reported on inhibitors of GSK-3 [30][31][32][33][34][35][36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 97%

“…The thought that GSK-3 inhibition could simultaneously arrest two or more diseases is compelling but naturally concerns over selectivity are crucial. Against this backdrop we feel strongly that there is a great need for rational drug design and have commenced steps in this direction [22].…”

Section: Introductionmentioning

confidence: 99%

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Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking

Sivaprakasam

Daga

Xie

et al. 2008

J Comput Aided Mol Des

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Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer's disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3alpha inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3alpha and GSK-3beta isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the beta isoform are the same in the alpha isoform, except that Asp133 in the beta isoform is replaced by Glu196 in the alpha isoform. We prepared a homology model for GSK-3alpha, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the beta isoform, and helped to explain the difference in their inhibitory activity.

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Section: Model Statisticssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 97%

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Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking

Sivaprakasam

Daga

Xie

et al. 2008

J Comput Aided Mol Des

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“…Further, Freude demonstrated that insulin receptor signaling and tau phosphorylation were completely abolished in the brains of the mice lacking the brain insulin receptor (NIRKO) under hyperinsulinemic conditions, indicating that the cerebral insulin receptors are a direct target of peripheral administered insulin. GSK-3 is a serine/threonine kinase that phosphorylates glycogen synthase in the rate-limiting step of glycogen biosynthesis [62] . GSK-3 have been implicated in the formation of neurofibrillary tangles [63,64] .…”

Section: Commonality Between T2dm and Admentioning

confidence: 99%

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer’s disease?

Lin

2007

Neurosci. Bull.

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Glucagon-like peptide-1 (GLP-1) has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus (T2DM). Both Alzheimer's disease (AD) and T2DM share some common pathophysiologic hallmarks, such as amyloid β (Aβ), phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Aβ and tau protein. Combine these findings, GLP-1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP-1, communities between T2DM and AD, new progresses of GLP -1 in treating T2MD and improving some pathologic hallmarks of AD.

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“…Rapid Overlay of Chemical Structures (ROCS) is a robust 3D ligand based virtual screening engine that perform alignments which are effective in a number of applications including lead and scaffold hop discovery, pose prediction, investigation of scaffold diversity, detection of shape-similar biologically active compounds, 3D QSAR, and structure-activity relationship (SAR) analysis [24][25][26][27] . Past QSAR investigations on 74 3-anilino-4-arylmaleimides showed that electronic and steric interactions at the 4-phenyl ring, electron-withdrawing groups at meta position and hydrophobic interactions at 3-anilino ring increase the biological activity 28,29 , whereas CoMFA studies featured fundamental ligand-receptor interactions [30][31][32] . CoMFA studies on bisarylmaleimides highlighted that bulky groups on the piperidine substituent (Figure 1), along with less voluminous substituents and electron-withdrawing group nearby carbonyl group linking piperidine increase the potency of maleimides (Figure 1a) 32 .…”

Section: Introductionmentioning

confidence: 99%

PLS and shape-based similarity analysis of maleimides – GSK-3 inhibitors

Crisan

Pacureanu

Avram

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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Context: Glycogen synthase kinase-3 (GSK-3) overactivity was correlated with several pathologies including type 2 diabetes mellitus, Alzheimer's disease, cancer, inflammation, obesity, etc. Objective: The aim of the current investigation was to model the inhibitory activity of maleimide derivatives -inhibitors of GSK-3, to evaluate the impact of alignment on statistical performances of the Quantitative Structure-Activity Relationship (QSAR) and the effect of the template on shape-similarity -binding affinity relationship. Materials and methods: Dragon descriptors were used to generate Projection to Latent Structures (PLS) models in order to identify the structural prerequisites of maleimides to inhibit GSK-3. Additionally, shape/volume structural analysis of binding site interactions was evaluated. Results: Reliable statistics R 2 YðCUMÞ ¼ 0.938/0.920, Q 2 YðCUMÞ ¼ 0.866/0.838 for aligned and alignment free QSAR models and significant (Pearson, Kendall and Spearman) correlations between shape/volume similarity and affinities were obtained. Discussion and conclusions: The crucial structural features modulating the activity of maleimides include topology, charge, geometry, 2D autocorrelations, 3D-MoRSE as well as shape/volume and molecular flexibility.

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Probing the physicochemical and structural requirements for glycogen synthase kinase-3α inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides

Cited by 38 publications

References 47 publications

Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking

Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer’s disease?

PLS and shape-based similarity analysis of maleimides – GSK-3 inhibitors

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