Thin water layers confined between surfaces are known for their surprising properties. Layered minerals, such as mackinawite, are naturally occurring systems where water is known to intercalate. Here we report, based on ab initio simulations, how excess protons can be hosted by the resulting nanostructured water film depending on the mackinawite interlayer distance. Even extreme nanoconfinement due to the mackinawite sheets is shown to not affect the dynamical nature of the topological defect, thus not localizing the excess protons but rather conserving the efficient structural (Grotthuss) diffusion process known in bulk water. Yet, depending on the width of the slit pore, the defect can bridge the bilayer water structure, thus forcing the excess proton into the water-depleted region between the bilayers.

The purpose of this study was to determine the cytochrome P450 1A2 (CYP1A2) inhibition potencies of structurally diverse compounds to create a comprehensive three-dimensional quantitative structure-activity relationship (3D-QSAR) model of CYP1A2 inhibitors and to use this model to predict the inhibition potencies of an external set of compounds. Fifty-two compounds including naphthalene, lactone and quinoline derivatives were assayed in a 96-well plate format for CYP1A2 inhibition activity using 7-ethoxyresorufin O-dealkylation as the probe reaction. The IC50 values of the tested compounds varied from 2.3 microM to over 40,000 microM. On the basis of this data set, a comparative molecular field analysis (CoMFA) and GRID/GOLPE models were created that yielded novel structural information about the interaction between inhibitory molecules and the CYP1A2 active site. The created CoMFA model was able to accurately predict inhibitory potencies of several structurally unrelated compounds, including selective inhibitors of other cytochrome P450 forms.

Wet iron-sulfur minerals have been shown to be ideal environments to allow for simple chemical reactions to occur in nature, for instance, in the framework of prebiotic chemistry. Yet, not much is known about such water/mineral interfaces beyond those involving pyrite, FeS(2), which is, however, chemically rather inert. In contrast, mackinawite is chemically reactive and consists of a layered crystal structure comprising FeS sheets that can be easily cleaved. Here, the properties of water confined between such sheets in lamella-like setups is investigated in the spirit of surface science model systems. The properties of this intercalated water are found to depend significantly on the interlayer distance and change from "arrested water" (in the limit of small interlayer distances) to liquid-like behavior.

A new inhibitor for human sirtuin type proteins 1 and 2 (SIRT1 and SIRT2) was discovered through virtual database screening in search of new scaffolds. A series of compounds was synthesized based on the hit compound (3-[[3-(4-tert-butylphenyl)1,2,4-oxadiazole-5-carbonyl]amino]-1-[3-(trifluoromethyl)phenyl]thiourea). The most potent compound in the series was nearly as potent as the reference compound (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide).

Sirtuins are NAD-dependent histone deacetylases, which cleave the acetyl-group from acetylated proteins, such as histones but also the acetyl groups from several transcription factors, and in this way can change their activities. Of all seven mammalian SirTs, the human sirtuin SirT1 has been the most extensively studied. However, there is no crystal structure or comparative model reported for SirT1. We have therefore built up a three-dimensional comparison model of the SirT1 protein catalytic core (domain area from residues 244 to 498 of the full length SirT1) in order to assist in the investigation of active site-ligand interactions and in the design of novel SirT1 inhibitors. In this study we also propose the binding-mode of recently reported set of indole-based inhibitors in SirT1. The site of interaction and the ligand conformation were predicted by the use of molecular docking techniques. To distinguish between active and inactive compounds, a post-docking filter based on H-bond network was constructed. Docking results were used to investigate the pharmacophore and to identify a filter for database mining.