Structure-activity relationships of pyrethroid insecticides. Part 2. The use of molecular dynamics for conformation searching and average parameter calculation

Summary Molecular dynamics simulations have been performed on a number of conformationally flexible pyrethroid insecticides. The results indicate that molecular dynamics is a suitable tool for conformational searching of small molecules given suitable simulation parameters. The structures derived from the simulations are compared with the static conformation used in a previous study. Various physicochemical parameters have been calculated for a set of conformations selected from the simulations using multivariate analysis. The averaged values of the parameters over the selected set (and the factors derived from them) are compared with the single conformation values used in the previous study.     

Unravelling the effect of the E545K mutation on PI3Kα kinase

PI3Kα controls several cellular processes and its aberrant signalling is implicated in tumorigenesis. One of its hotspot mutations, E545K, increases PI3Kα lipid kinase activity, but its mode of action is only partially understood. Here, we perform biased and unbiased molecular dynamics simulations of PI3Kα and uncover, for the first time, the free energy landscape of the E545K PI3Kα mutant. We reveal the mechanism by which E545K leads to PI3Kα activation in atomic-level detail, which is considerably more complex than previously thought.

The mechanism by which the cancer-causing E545K mutation may lead to PI3Kα activation is described in atomic-level detail.     

Photoactive metallocyclodextrins: sophisticated supramolecular arrays for the construction of light activated miniature devices

The introduction of photoactive metal centres onto cyclodextrin receptors opens up new possibilities for the design of sensors, wires and energy conversion systems. This tutorial review focuses on strategies involving such metallocyclodextrins for the construction of supramolecular arrays with light-activated functions. The assembly procedures for building such arrays are presented, together with the features required for their functions both as sensors for ion or small molecule detection and as wires for photoinduced long-range energy or electron transport. Systems for metal ion sensing are described where the cyclodextrin plays a mediating role in influencing the luminescence properties of an organic probe, responsive to metal binding. Small molecule sensing by the cyclodextrin cavity is realised using luminescent lanthanide or transition metal functionalised cyclodextrins. The light signal of the photoactive metal is switched on or off upon binding an analyte in the cyclodextrin cavity. The metallocyclodextrin systems that function as wires are distinguished by the controlled assembly of transition metal polypyridine and metalloporphyrin units. These units have inherent photoactivity that defines the vectorial direction of energy or electron transfer processes through the wire.     

9,9-diphenyl-1,9,10,10a-tetrahydro-2H-phenaleno[1,9-bc]pyrans

Reaction between some naphtho[2,1-b]pyrans and 1,1-diphenylethene affords 9,9-diphenyl-1,9,10,10a-tetrahydro-2H-phenaleno[1,9-bc]pyrans.     

Determination of Total Reduced Thiol Levels in Plasma Using a Bromide Substituted Quinone

The exploitation of 2‐bromo‐1,4‐naphthoquinone (NQBr) as a selective redox label for the determination of reduced thiol functionalities (RSH) has been investigated. The system is selective for RSH functionality, giving distinct voltammetric signals for glutathione and cysteine but can also be adapted for broad spectrum thiol detection. Ion chromatographic protocols based on conductimetric detection enable total RSH analysis (protein and monomolecular moieties) within human plasma. Bromide released through the reaction can be easily quantified and integrated within normal IC measurements. The efficacy of the approach has been assessed and the response validated through comparison with the standard colorimetric technique.     

Lanthanide chelates of fluorinated β-diketones. Part III. Mass spectra of lanthanide chelates of five fluorinated β-diketones

Summary The mass spectra of sixty lanthanide chelates of the fluorinated -diketones RC(OH)=CHCOCF₃ (R=2-theonyl,p-BrC₆H₄,m-MeC₆H₄,o-MeC₆H₄, and Bu-t) have been obtained. The mass spectra were essentially similar, in contrast to those found ford-block transition metal chelates. Valency change from 3 to 2 occurred with samarium (4f ⁵), europium (4f ⁶), thulium (4f ¹²), and ytterbium (4f ¹³); the intensity of the Met(II)-containing peaks varied: Eu Sm > Yb > Tm, reflecting the decreasing tendency of these lanthanides to display bivalency. Valency change from 4 to 3 was observed with cerium (4f¹) but not with terbium (4f⁸).Part II,Transition Met. Chem., 9, 423 (1984).     

UV-Induced 1,3,4-Oxadiazole Formation from 5-Substituted Tetrazoles and Carboxylic Acids in Flow

A range of 1,3,4-oxadiazoles have been synthesized using a UV-B activated flow approach starting from carboxylic acids and 5-substituted tetrazoles. The application of UV light represents an attractive alternative to the traditional thermolytic approach and has demonstrated comparable efficiency and versatility, with a diverse substrate scope, including the incorporation of highly substituted amino acids.     

Polynomial neural network for linear and non-linear model selection in quantitative-structure activity relationship studies on the internet

This article presents a self-organising multilayered iterative algorithm that provides linear and non-linear polynomial regression models thus allowing the user to control the number and the power of the terms in the models. The accuracy of the algorithm is compared to the partial least squares (PLS) algorithm using fourteen data sets in quantitative-structure activity relationship studies. The calculated data show that the proposed method is able to select simple models characterized by a high prediction ability and thus provides a considerable interest in quantitative-structure activity relationship studies. The software is developed using client-server protocol (Java and C++ languages) and is available for world-wide users on the Web site of the authors.     

Pattern recognition display methods for the analysis of computed molecular properties

Summary Pattern recognition methods, particularly the unsupervised learning techniques, are well suited for the preliminary analysis of the large data sets produced by computer chemistry. The use of linear and non-linear display methods for such exploratory analysis are exemplified with the aid of two data sets of biologically active molecules. Advantages and disadvantages of these techniques are discussed.