Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

New stand magnifiers do not meet rated levels of performance

A new range of stand magnifiers has been released by the COIL company in the United Kingdom. Examination of these magnifiers reveals that they fail to deliver the rated magnifications labelled prominently on the appliances, as a result of the manufacturer's conformance with the requirements of the German DIN standard and the use of back vertex power (F'_v) rather than equivalent dioptric power (F_m) of the magnifier. In this study we provide information on the optometric parameters of these new stand magnifiers that will assist the more accurate specification of improvements in vision expected from their use.     

Chemiluminescence from Acetaldehyde Oxidation by Xanthine Oxidase Involves Generation of and Interactions with Hydroxyl Radicals

The ability of acetaldehyde to generate free radicals is often ascribed to its oxidation by xanthine oxidase, with the subsequent production of reactive oxygen intermediates. Chemiluminescence associated with the oxidation of acetaldehyde by xanthine oxidase was inhibited by superoxide dismutase, catalase, or several hydroxyl radical scavenging agents, and was stimulated by the addition of EDTA or ferric-EDTA. This suggests that the light emission is primarily due to the production of hydroxyl radicals via an iron-catalyzed Haber-Weiss type of reaction. Chemiluminescence with hypoxanthine as substrate for xanthine oxidase was much lower than that found with acetaldehyde, yet rates of hydroxyl radical production were greater with hypoxanthine. Acetaldehyde increased light emission in the presence of hypoxanthine by a greater than additive effect. These results suggest a complex role for acetaldehyde in catalyzing xanthine oxidase-dependent chemiluminescence. It appears that besides being a substrate for xanthine oxidase, acetaldehyde also reacts with the generated hydroxyl radical to produce acetaldehyde radicals, which yield chemiluminescence upon their decay. Further studies will be required to evaluate whether the production of such species contributes to or plays a role in the generation of reactive oxygen intermediates and toxicity associated with acetaldehyde metabolism.