In this study, the binding modes of a-conotoxin ImI to the alpha 7-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some Apoptosis Compound Library nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent

dielectric constant or explicit water, or molecular dynamics using five restraint

strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R 2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of alpha-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and GSK1904529A purchase chemically modified aconotoxins.”
“Low-dose aspirin (325 mg or less) alone and in combination with other antiplatelet agents is widely used for the management of cardiovascular disease. Although the risk with low-dose aspirin alone is less than Nonsteroidal anti-inflammatory drugs (NSAIDs), given widespread use, aspirin related toxicity has become a substantial health care problem due to acute and chronic GI bleeding. SCH 900776 solubility dmso A variety of strategies are currently available to minimize the risk of developing upper GI side effects

of aspirin. Agents that have efficacy include oral prostaglandin analogues. H2 receptor antagonists and proton pump inhibitors. PPIs appear to be the most effective strategy, with the least side effects and the convenience of once daily dosing. The substitution of another antiplatelet agent such as clopidogrel for aspirin alone does not appear to provide a safer alternative to low-dose aspirin for patients at GI risk. Small bowel injury can occur with aspirin and can be assessed with capsule endoscopy; however, no strategy is known to reduce this potential toxicity in clinical practice. (C) 2012 Elsevier Ltd. All rights reserved.”
“Introduction and objectives: Drug-eluting stents are useful for preventing restenosis, but the patho-physiological processes involved in the proliferative response after implantation are still not known in detail.