Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Molecular modeling was used to analyze the binding mode and activities of histamine H₃ receptor antagonists. A model of the H₃ receptor was constructed through homology modeling methods based on the crystal structure of bovine rhodopsin. Known H₃ antagonists were interactively docked into the putative antagonist binding pocket and the resultant model was subjected to molecular mechanics energy minimization and molecular dynamics simulations which included a continuum model of the lipid bilayer and intra- and extracellular aqueous environments surrounding the transmembrane helices. The transmemebrane helices stayed well embedded in the dielectric slab representing the lipid bilayer and the intra- and extracellular loops remain situated in the aqueous solvent region of the model during molecular dynamics simulations of up to 200 ps in duration. A pharmacophore model was calculated by mapping the features common to three active compounds three-dimensionally in space. The 3D pharmacophore model complements our atomistic receptor/ligand modeling. The H₃ antagonist pharmacophore consists of two protonation sites (i.e. basic centers) connected by a central aromatic ring or hydrophobic region. These two basic sites can simultaneously interact with Asp 114 (3.32) in helix III and a Glu 206 (5.46) in helix V which are believed to be the key residues that histamine interacts with to stabilize the receptor in the active state. The interaction with Glu 206 is consistent with the enhanced activity resulting from the additional basic site. In addition to these two salt bridging interactions, the central region of these antagonists contains a lipophilic group, usually an aromatic ring, that is found to interact with several nearby hydrophobic side chains. The picture of antagonist binding provided by these models is consistent with earlier pharmacophore models for H₃ antagonists with some exceptions.     

Features of a Power System Incorporating Large AC Motors/Captive Transformers

Both synchronous and induction motors driving fans, pumps, and compressors (variable torque types of loads) may prove to be more economical and reliable when utilizing a lower voltage motor plus a captive transformer rather than a 13.8-kV motor. The economic factors, matching motor capabilities to load requirements, power system considerations, relaying and grounding systems possibilities, and operating experience with installed drives in Atlantic Richfield's Philadelphia Refinery are covered.     

Corrosion behaviour of magnetron sputtered α- and β-Ta coatings on AISI 4340 steel as a function of coating thickness

The corrosion behaviour of magnetron sputtered α- and β-Ta coated AISI 4340 steels was studied with potentiodynamic polarization and electrochemical impedance spectroscopy. The coating porosity was observed to decrease with increasing coating thickness. For coatings less than 10 μm thick (α- or β-Ta), porosity was significant and open pores resulted in severe localized corrosion of the steel substrate, coating delamination, and overall coating failure. Additionally, the β-Ta coatings were more susceptible than the α-phase to delamination. As for the 50 and 100 μm thick α-Ta coatings, the electrochemical impedance behaviour was comparable to that of Ta foil, demonstrating the coating viability and corrosion resistance.     

Heterogeneous catalysis: looking forward with molecular simulation

Some of the areas in which we anticipate, over the next five years, notable advances in the application of molecular simulation to problems in heterogeneous catalysis are considered, in the context of recent progress to date. The areas specifically addressed are:

• expanding access to methods,

• quantitative structure-property relationships,

• building structural models to focus or pre-screen experiments,

• confidence in predicting local and extended structure

• reaction mechanisms, barriers and kinetics, and

• data for chemical process simulations.

In each of these areas, we indicate why we consider the topic significant, provide reference to topical work and suggest opportunities for future developments.