The effect of Li+ on GSK-3 inhibition: molecular dynamics simulation.

Glycogen synthase kinase-3 (GSK-3) is a kind of serine-threonine protein kinase. It places important roles in several signaling pathways and it is a key therapeutic target for a number of diseases, such as diabetes, cancer, Alzheimer's disease and chronic inflammation. Mg(2+) ions which interact with ATP are conserved in GSK. They are important in phosphoryl transfer. Li(+) is an inhibitor for GSK-3. It is used to treat bipolar mood disorder. This paper illustrates the effect of Li(+) on GSK-3. When Mg(I)(2+) is replaced by Li(+), the atom fluctuation of GSK-3 will rise, and the in-line phosphoryl transfer mechanism is probably demolished and the binding of pre-phosphorylated substrates may be disturbed. All the results we obtained clearly suggest that inhibition to GSK-3 is caused by the Mg(I)(2+) replacement with Li(+).

Effect of mutation K85R on GSK-3beta: Molecular dynamics simulation.

As a serine-threonine protein kinase, glycogen synthase kinase-3 (GSK-3) regulates the synthesis of glycogen and plays important roles in several signaling pathways. It is a key therapeutic target for a number of diseases, such as diabetes, cancer, Alzheimer's disease and chronic inflammation. The conserved Lys85 is important to GSK-3beta activity and in this paper we illustrate the significant role of Lys85 using dynamic simulation. We find that when Lys85 is mutated to Arg, one of the two conserved hydrogen bonds between Lys85 and ATP disappears, the salt bridge between Lys85 and Glu97 cannot form, and conformational changes of Phe93, Arg96 and Glu211 occur. These will cause conformational changes of the substrate binding groove that would inhibit the activity of GSK-3beta. MM-GBSA calculations reveal that the K85R mutation could lead to a less energy-favorable complex, which is consistent with the structural analysis.

A novel tetranuclear copper(I) sulfanide complex with bis(diphenylphosphino)amine.

The title novel mixed mu(2)-SH- and mu(3)-SH-bridged tetranuclear copper(I) complex, cyclo-bis[mu(2)-bis(diphenylphosphino)amine]di-mu(3)-sulfanido-di-mu(2)-sulfanido-tetracopper(I) methanol disolvate, [Cu(4)(SH)(4)(C(24)H(21)NP(2))(2)].2CH(3)OH, has crystallographically imposed centrosymmetry and affords a neutral Cu(4)S(4) core with a distorted step-like structure. The distances of 2.8458 (16) and 2.8179 (16) A between copper(I) centres indicate the presence of ligand-supported Cu...Cu interactions. Strong N-H...O and O-H...S hydrogen bonds between the tetranuclear cluster and methanol solvent molecules result in a two-dimensional hydrogen-bonded supramolecular network. This complex is the first example of a coinage tetranuclear metal complex with mixed mu(2)-SH- and mu(3)-SH-bridged chromophores.

Three-dimensional QSAR of HPPD inhibitors, PSA inhibitors, and anxiolytic agents: effect of tautomerism on the CoMFA models.

The present study was design to examine the effect of tautomerism upon the CoMFA results. Three selected data sets involving protropic tautomerism, which are 21 p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, 35 inhibitors of puromycin-sensitive aminopeptidase (PSA), and 67 anxiolytic agents, were used for this purpose. Atom-by-atom alignment technique was adopted to superimpose the molecules in the data sets onto a template. The structural alignments using different tautomeric forms had no significant difference except the atoms involved in tautomerism, which ensures, to a great extent, that the differences of the CoMFA results result primarily from the tautomerism. All-orientation and all-placement search (AOS-APS) based CoMFA models, in addition to the conventional ones, were derived for each system and proved to be capable of yielding much improved statistical results. In the cases of the data sets of HPPD inhibitors and PSA inhibitors, excellent AOS-APS CoMFA models (q2>0.8 with four components for the former and q2>0.7 with seven components for the latter) were obtained, and almost no significant difference in statistical quality was observed when using different tautomeric forms to derive the models. However, it was not the case when treating the data set of anxiolytic agents. The keto tautomer, which was the active form of the PBI type inhibitors, produced measurably better results (q2=0.54 with eight components) than that the enol one (q2=0.37 with five components), indicating the importance of selecting proper tautomer in the CoMFA studies. Furthermore, there existed some substantial differences of the electrostatic field contours between the two different tautomeric forms for all of the three systems considered, whereas the differences in the steric field contour maps were limited. This implies that the resulting new potent ligands may be quite different if one utilizes the CoMFA models of different tautomeric forms for guiding further structural refinements.