A novel small-molecule inhibitor of IL-6 signalling.

A small library of pyrrolidinesulphonylaryl molecules has been synthesized via an efficient 4-step route, and members evaluated for their ability to inhibit IL-6 signalling. One molecule (6a) was found to have promising activity against IL-6/STAT3 signalling at the low micromolar level, and to selectively inhibit phosphorylation of STAT3 (but not STAT1) in IL-6 stimulated MDA-MB-231 breast cancer and HeLa cell lines. It was also selectively cytostatic in MDA-MB-231 (STAT3-dependent) versus A4 (STAT3-null) cells suggesting STAT3-specific inhibitory properties.

Characterization of protein conformational states by normal-mode frequencies.

Conformational change in polymers including proteins is central to many molecular processes. Defining conformational states, however, remains a difficult and increasingly common problem, with many existing methods based on arbitrary or potentially unrepresentative measures. Furthermore, the expanding length of molecular dynamics simulations and direct observation of transitions between different energy basins suggest that this issue will only become evermore important.

In silico mutation of cysteine residues in the ligand-binding domain of an N-methyl-D-aspartate receptor.

The precise nature of redox modulation of N-methyl-d-aspartate (NMDA) receptors is still unclear, although it is thought to be related to the formation and breaking of disulfide bonds. Recent structural data demonstrated the way in which disulfide bonds in the ligand-binding core of the NR1 subunit are arranged. However, the structures were not able to reconcile existing experimental data that examined the effects of mutating these cysteine residues.

Molecular dynamics simulations of the ligand-binding domain of an N-methyl-D-aspartate receptor.

The mechanism of partial agonism at N-methyl-D-aspartate receptors is an unresolved issue, especially with respect to the role of protein dynamics. We have performed multiple molecular dynamics simulations (7 x 20 ns) to examine the behavior of the ligand-binding core of the NR1 subunit with a series of ligands. Our results show that water plays an important role in stabilizing different conformations of the core and how a closed cleft conformation of the protein might be stabilized in the absence of ligands.