Author
K.-M. Alexacou
Bio: K.-M. Alexacou is an academic researcher from China Pharmaceutical University. The author has contributed to research in topics: Glycogen phosphorylase & Ligand (biochemistry). The author has an hindex of 8, co-authored 9 publications receiving 495 citations.
Papers
More filters
••
TL;DR: Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition.
Abstract: Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity (7, 18−20) or no activity (21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb−asiatic acid and GPb−maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition.
187 citations
••
TL;DR: The synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed and have the potential to facilitate structure-based drug design.
Abstract: The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention Glycogen phosphorylase is a typical allosteric protein with five different ligand binding sites, thus offering multiple opportunities for modulation of enzyme activity The present survey is focused on recent new molecules, potential inhibitors of the enzyme The biological activity can be modified by these molecules through direct binding, allosteric effects or other structural changes Progress in our understanding of the mechanism of action of these inhibitors has been made by the determination of high-resolution enzyme inhibitor structures (both muscle and liver) The knowledge of the three-dimensional structures of protein-ligand complexes allows analysis of how the ligands interact with the target and has the potential to facilitate structure-based drug design In this review, the synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed
133 citations
••
TL;DR: In this paper, the same azide and substituted acetylenes gave 1-(β-d -glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide-alkyne cycloadditions.
Abstract: Per-O-acetylated β- d -glucopyranosyl azide was transformed into an intermediate iminophosphorane by PMe 3 which was then acylated to N -acyl-β- d -glucopyranosylamines. The same azide and substituted acetylenes gave 1-(β- d -glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide–alkyne cycloadditions. Deprotection of these products by the Zemplen method furnished β- d -Glc p -NHCO-R derivatives as well as 1-(β- d -Glc p )-4-R-1,2,3-triazoles which were evaluated as inhibitors of rabbit muscle glycogen phosphorylase b. Pairs of amides versus triazoles with the same R group displayed similar inhibition constants. X-ray crystallographic studies on the enzyme–inhibitor complexes revealed high similarities in the binding of pairs with R = 2-naphthyl and hydroxymethyl, while for the R = Ph and 1-naphthyl compounds a different orientation of the aromatic part and changes in the conformation of the 280s loop were observed. By this study new examples of amide-1,2,3-triazole bioisosteric relationship have been provided.
61 citations
••
TL;DR: Docking calculations with GLIDE in extra-precision (XP) mode yielded excellent agreement with experiment, as judged by comparison of the predicted binding modes of the five ligands with the crystallographic conformations and the good correlation between the docking scores and the experimental free binding energies.
59 citations
••
TL;DR: In this article, the structure of GPb in complex with glucosyltriazolylacetamide at 100 K to 188 A resolution was determined, with and without the crystallographic ordered cavity waters using the GoldScore scoring function.
Abstract: 4-Phenyl-N-(beta-D-glucopyranosyl)-1H-1,2,3-triazole-1-acetamide (glucosyltriazolylacetamide) has been studied in kinetic and crystallographic experiments with glycogen phosphorylase b (GPb), in an effort to utilize its potential as a lead for the design of potent antihyperglycaemic agents Docking and molecular dynamics (MD) calculations have been used to monitor more closely the binding modes in operation and compare the results with experiment Kinetic experiments in the direction of glycogen synthesis showed that glucosyltriazolylacetamide is a better inhibitor (K(i) = 018 mM) than the parent compound alpha-D-glucose (K(i) = 17 mM) or beta-D-glucose (K(i) = 74 mM) but less potent inhibitor than the lead compound N-acetyl-beta-D-glucopyranosylamine (K(i) = 32 microM) To elucidate the molecular basis underlying the inhibition of the newly identified compound, we determined the structure of GPb in complex with glucosyltriazolylacetamide at 100 K to 188 A resolution, and the structure of the compound in the free form Glucosyltriazolylacetamide is accommodated in the catalytic site of the enzyme and the glucopyranose interacts in a manner similar to that observed in the GPb-alpha-D-glucose complex, while the substituent group in the beta-position of the C1 atom makes additional hydrogen bonding and van der Waals interactions to the protein A bifurcated donor type hydrogen bonding involving O3H, N3, and N4 is seen as an important structural motif strengthening the binding of glucosyltriazolylacetamide with GP which necessitated change in the torsion about C8-N2 bond by about 62 degrees going from its free to the complex form with GPb On binding to GP, glucosyltriazolylacetamide induces significant conformational changes in the vicinity of this site Specifically, the 280s loop (residues 282-288) shifts 07 to 31 A (CA atoms) to accommodate glucosyltriazolylacetamide These conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding compared with the lead compound In the molecular modeling calculations, the GOLD docking runs with and without the crystallographic ordered cavity waters using the GoldScore scoring function, and without cavity waters using the ChemScore scoring function successfully reproduced the crystallographic binding conformation However, the GLIDE docking calculations both with (GLIDE XP) and without (GLIDE SP and XP) the cavity water molecules were, impressively, further able to accurately reproduce the finer details of the GPb-glucosyltriazolylacetamide complex structure The importance of cavity waters in flexible receptor MD calculations compared to "rigid" (docking) is analyzed and highlighted, while in the MD itself very little conformational flexibility of the glucosyltriazolylacetamide ligand was observed over the time scale of the simulations
31 citations
Cited by
More filters
01 Feb 1995
TL;DR: In this paper, the unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio using DFT, MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set.
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
1,652 citations
••
1,395 citations
••
TL;DR: This review highlights the successful advancement of Cu(I)-catalyzed click chemistry in glycoscience and its applications as well as future scope in different streams of applied sciences.
Abstract: Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC), popularly known as the “click reaction”, serves as the most potent and highly dependable tool for facile construction of simple to complex architectures at the molecular level. Click-knitted threads of two exclusively different molecular entities have created some really interesting structures for more than 15 years with a broad spectrum of applicability, including in the fascinating fields of synthetic chemistry, medicinal science, biochemistry, pharmacology, material science, and catalysis. The unique properties of the carbohydrate moiety and the advantages of highly chemo- and regioselective click chemistry, such as mild reaction conditions, efficient performance with a wide range of solvents, and compatibility with different functionalities, together produce miraculous neoglycoconjugates and neoglycopolymers with various synthetic, biological, and pharmaceutical applications. In this review we highlight the successful advancement of Cu(I)...
557 citations
••
TL;DR: An overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples.
392 citations
••
TL;DR: 4-amino-N-((1-dodecyl-1H-1,2,3-triazol-4-yl)methyl) benzenesulfonamide were found to be the most potent compounds against all the tested strains except for Candida albicans and Candida mycoderma.
320 citations