Tibor Docsa

Bio: Tibor Docsa is an academic researcher from University of Debrecen. The author has contributed to research in topics: Glycogen phosphorylase & Glycogen synthase. The author has an hindex of 24, co-authored 68 publications receiving 1729 citations. Previous affiliations of Tibor Docsa include Hungarian Academy of Sciences.

Glucose Analog Inhibitors of Glycogen Phosphorylases as Potential Antidiabetic Agents: Recent Developments

Abstract: Diabetes is among the largest contributors to global mortality through its long term complications. The worldwide epidemic of type 2 diabetes has been stimulating the quest for new concepts and targets for the treatment of this incurable disease. A new target is glycogen phosphorylase (GP), the main regulatory enzyme in the liver responsible for the control of blood glucose levels. One of several approaches to influence the action of GP is the use of glucose derivatives as active site inhibitors. This field of research commenced 10-15 years ago and, due to joint efforts in computer aided molecular design, organic synthesis, protein crystallography, and biological assays, resulted in glucopyranosylidene-spiro-hydantoin 16 (Ki = 3-4 μM) as the most efficient glucose analog inhibitor of GP of that time. The present paper surveys the recent developments of this field achieved mainly in the last five years: the synthesis and evaluation of glucopyranosylidene-spiro-thiohydantoin 18 (Ki = 5 μM) which has proven equipotent with 16, and is available in gram amounts; furanosylidene- and xylopyranosylidene-spiro-(thio)hydantoins whose ineffectiveness (Ki > 10 μM) confirmed the high specificity of the catalytic site of GP towards the D-glucopyranosyl unit; “open” hydantoins like methyl N-(1-carboxamido-D-glucopyranosyl)carbamate 37 (Ki = 16 > M) and N-acyl-N-(β-Dglucopyranosyl) ureas among them the to date best glucose analog inhibitor N-(2-naphthoyl)-N-(β-D-glucopyranosyl)urea (35, Ki = 0.4 μM) which can also bind to the so-called new allosteric site of GP; C-(β-D-glucopyranosyl)heterocycles (tetrazole, 1,3,4-oxadiazoles, benzimidazole (Ki = 11 μM), and benzothiazole). Iminosugars like isofagomine (45, IC50 = 0.7 μM), noeuromycin (53, IC50 = 4 μM), and azafagomine (54, IC50 = 13.5 μM) also bind strongly to the active site of GP, however, substitution on the nitrogens makes the binding weaker. The natural product five-membered iminosugar DAB (56) exhibited IC50 ∼ 0.4-0.5 μM. Azoloperhydropyridines which can be regarded iminosugar-annelated heterocycles show moderate inhibition of GP: nojiritetrazole 12 (Ki = 53 μM) is the best inhibitor and fewer nitrogens in the five-membered ring weakens the binding. Physiological investigations have been carried out with N-acetyl-β-Dglucopyranosylamine 6, spiro-thiohydantoin 18, isofagomine 45, and DAB 56 to underline the potential use of these compounds in the treatment of type 2 diabetes. Computational methods suggest to synthesize further anomerically bifunctional glucose derivatives which may be good inhibitors of GP.

Synthesis of and a Comparative Study on the Inhibition of Muscle and Liver Glycogen Phosphorylases by Epimeric Pairs of d-Gluco- and d-Xylopyranosylidene-spiro-(thio)hydantoins and N-(d-Glucopyranosyl) Amides

Abstract: d-Gluco- and d-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure In the key step of t

Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site.

Abstract: Glycogen phosphorylase (GP), because of its central role in glycogen metabolism, has been exploited as a potential target for structure-based design of potent inhibitors, that may be relevant to the control of blood glucose concentrations in type 2 diabetes (Aiston et al. 2001, 2003; Latsis et al. 2002). Several regulatory binding sites, identified in GP, have been used as molecular targets (for review, see Oikonomakos 2002). These are the allosteric site that binds the activator AMP and the inhibitor glucose-6-P, the catalytic site that binds substrates glucose-1-P and glycogen, and the inhibitor glucose, the caffeine binding site, which binds caffeine and related compounds, and the new allosteric inhibitor or indole binding site that binds indole-2 carboxamides and β-D-glucopyranosyl ureas. More specifically, the catalytic site has been probed with glucose analog inhibitors, designed on the basis of information derived from the crystal structure of T-state GPb–α-D-glucose complex (Martin et al. 1991; Watson et al. 1994, 1995; Bichard et al. 1995; Oikonomakos et al. 1995, 2002a, b; Gregoriou et al. 1998; Somsak et al. 2001, 2003; Chrysina et al. 2003, 2004; Gyorgydeak et al. 2004). A common feature of these compounds is that upon binding at the catalytic site, they promote the (less active) T-state conformation of the enzyme through stabilization of the closed position of 280s loop (residues 282–287), which blocks access of the substrate to the catalytic site. We report here on the kinetic and crystallographic study of three new lead compounds, derivatives of β-D-glucopy-ranose, 2-(β-D-glucopyranosyl)-5-methyl-1,3,4-oxadiazole, 2-(β-D-glucopyranosyl)-benzothiazole, and 2-(β-D-gluco-pyranosyl)-benzimidazole with GPb. The kinetic experiments reveal that the three compounds are potent competitive inhibitors with respect to the substrate Glc-1-P, whereas the crystallographic results show that each of the compounds binds at the catalytic site and stabilizes the closed position of the 280s loop. Additionally, benzimidazole can occupy the indole binding site and also a novel site that has not been observed previously. Benzimidazole is the first compound to show binding at this novel site.

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

Abstract: : The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]

Abstract: Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity.

Abstract: Described is a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives. The reactions tolerate a broad range of functionality and proceed in high yield in organic solvents, water, cell media, or cell lysate. The rate of the ligation between trans-cyclooctene and 3,6-di-(2-pyridyl)-s-tetrazine is very rapid (k2 2000 M−1 s−1). This fast reactivity enables protein modification at low concentration.

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Abstract: The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of 'click chemistry' due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.