van der Waals interactions govern C-β-d-glucopyranosyl triazoles’ nM inhibitory potency in human liver glycogen phosphorylase

Kantsadi, A.L.; Stravodimos, G.A.; Kyriakis, E.; Chatzileontiadou, D.S.M.; Solovou, T.G.A.; Kun, Sándor; Bokor, Éva; Somsák, László; Leonidas, D.D.

doi:10.1016/j.jsb.2017.05.001

Cited by 17 publications

(32 citation statements)

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“…The inhibition constant value (K i ) of the synthesized compounds for human liver glycogen phosphorylase a (hlGPa) together with the values for rmGPa (to compare the effect of the compounds in the liver and muscle) and rmGPb (to validate structural data) are summarized in Table 4. As the data shows for rmGPb, inhibitors Each of the inhibitors binds at the catalytic site by anchoring the glucose moiety at a location previously observed for α-D-glucose and other glucose-based inhibitors [20,[46][47][48][49][50]. There the glucose moiety engages in hydrogen bonding (Table 5) and van der Waals interactions almost identical to those that have been previously observed for similar glucose analogues.…”

Section: Enzyme Kineticssupporting

confidence: 56%

A multidisciplinary study of 3-(β- d -glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

Kun

Begum

Kyriakis

et al. 2018

European Journal of Medicinal Chemistry

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3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with K's < 10 μM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-β-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(β-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(β-d-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low μM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles.

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Section: Enzyme Kineticssupporting

confidence: 56%

A multidisciplinary study of 3-(β- d -glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

Kun

Begum

Kyriakis

et al. 2018

European Journal of Medicinal Chemistry

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“…RmGP and hlGP share 97% sequence homology and both enzymes are fully conserved in sequence and structure at the active site; thus, any structural analysis of rmGPb is applicable to hlGP. This has been demonstrated in several inhibitor studies (Kantsadi et al, 2016(Kantsadi et al, , 2017Bokor et al, 2017;Kyriakis et al, 2018Kyriakis et al, , 2020Chetter et al, 2020;Fischer et al, 2019). In the last 30 years many inhibitor studies have been reported which have led to the discovery of potent and specific GP inhibitors (Oikonomakos, 2002;Somsá k et al, 2008;Somsá k, 2011;Stravodimos et al, 2017;Hayes et al, 2014).…”

Section: Introductionmentioning

confidence: 90%

Glycogen phosphorylase revisited: extending the resolution of the R- and T-state structures of the free enzyme and in complex with allosteric activators

Leonidas

Zographos

Tsitsanou

et al. 2021

Acta Crystallogr F Struct Biol Commun

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The crystal structures of free T-state and R-state glycogen phosphorylase (GP) and of R-state GP in complex with the allosteric activators IMP and AMP are reported at improved resolution. GP is a validated pharmaceutical target for the development of antihyperglycaemic agents, and the reported structures may have a significant impact on structure-based drug-design efforts. Comparisons with previously reported structures at lower resolution reveal the detailed conformation of important structural features in the allosteric transition of GP from the T-state to the R-state. The conformation of the N-terminal segment (residues 7–17), the position of which was not located in previous T-state structures, was revealed to form an α-helix (now termed α0). The conformation of this segment (which contains Ser14, phosphorylation of which leads to the activation of GP) is significantly different between the T-state and the R-state, pointing in opposite directions. In the T-state it is packed between helices α4 and α16 (residues 104–115 and 497–508, respectively), while in the R-state it is packed against helix α1 (residues 22′–38′) and towards the loop connecting helices α4′ and α5′ of the neighbouring subunit. The allosteric binding site where AMP and IMP bind is formed by the ordering of a loop (residues 313–326) which is disordered in the free structure, and adopts a conformation dictated mainly by the type of nucleotide that binds at this site.

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“…After O -peracetylation (method e ) of the mixture the products could be separated and identified as 4c and a partially saturated derivative 4d . Since the formation of a tetrahydronaphthyl by-product under catalytic hydrogenation was observed previously with a 2-naphthyl substituted C -glucopyranosyl 1,2,4-triazole [ 50 ] hydrogenolytic deprotection of 2b was not attempted. Instead, the protecting groups were exchanged to acetate esters as reported to get O -peracetylated acetylene 3 [ 51 ] .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase

et al. 2018

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The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-d-glucopyranosyl ethynes and aryl azides. 1-β-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-β-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide to give N-β-d-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-d-glucopyranosyl-5-phenyltetrazole (IC50 600 μM). These studies extended the structure-activity relationships of β-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.

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van der Waals interactions govern C-β-d-glucopyranosyl triazoles’ nM inhibitory potency in human liver glycogen phosphorylase

Cited by 17 publications

References 50 publications

A multidisciplinary study of 3-(β- d -glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

A multidisciplinary study of 3-(β- d -glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

Glycogen phosphorylase revisited: extending the resolution of the R- and T-state structures of the free enzyme and in complex with allosteric activators

Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase

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