Evaluation of a novel virtual screening strategy using receptor decoy binding sites

Virtual screening is used in biomedical research to predict the binding affinity of a large set of small organic molecules to protein receptor targets. This report shows the development and evaluation of a novel yet straightforward attempt to improve this ranking in receptor-based molecular docking using a receptor-decoy strategy. This strategy includes defining a decoy binding site on the receptor and adjusting the ranking of the true binding-site virtual screen based on the decoy-site screen. The results show that by docking against a receptor-decoy site with Autodock Vina, improved Receiver Operator Characteristic Enrichment (ROCE) was achieved for 5 out of fifteen receptor targets investigated, when up to 15 % of a decoy site rank list was considered. No improved enrichment was seen for 7 targets, while for 3 targets the ROCE was reduced. The extent to which this strategy can effectively improve ligand prediction is dependent on the target receptor investigated

Influenza A nucleoprotein binding sites for antivirals: current research and future potential

This document is the Accepted Manuscript version of the following article: Andreas Kukol and Hershna Patel, ‘Influenza A nucleoprotein binding sites for antivirals: current research and future potential’, Future Biology, Vol 9(7): 625-627, July 2014. The version of record is available online at doi: 10.2217/fvl.14.45Peer reviewedFinal Accepted Versio

Evolutionary conservation of influenza A PB2 sequences reveals potential target sites for small molecule inhibitors.

The influenza A basic polymerase protein 2 (PB2) functions as part of a heterotrimer to replicate the viral RNA genome. To investigate novel PB2 antiviral target sites, this work identified evolutionary conserved regions across the PB2 protein sequence amongst all sub-types and hosts, as well as ligand binding hot spots which overlap with highly conserved areas. Fifteen binding sites were predicted in different PB2 domains; some of which reside in areas of unknown function. Virtual screening of ~50,000 drug-like compounds showed binding affinities of up to 10.3 kcal/mol. The highest affinity molecules were found to interact with conserved residues including Gln138, Gly222, Ile529, Asn540 and Thr530. A library containing 1738 FDA approved drugs were screened additionally and revealed Paliperidone as a top hit with a binding affinity of -10 kcal/mol. Predicted ligands are ideal leads for new antivirals as they were targeted to evolutionary conserved binding sites

Predicting Axonal Response to Molecular Gradients with a Computational Model of Filopodial Dynamics

Axons are often guided to their targets in the developing nervous system by attractive or repulsive molecular concentration gradients. We propose a computational model for gradient sensing and directed movement of the growth cone mediated by filopodia. We show that relatively simple mechanisms are sufficient to generate realistic rajectories for both the short-term response of axons to steep gradients and the long-term response of axons to shallow gradients. The model makes testable predictions for axonal response to attractive and repulsive gradients of different concentrations and steepness, the size of the intracellular amplification of the gradient signal, and the differences in intracellular signaling required for repulsive versus attractive turning

Elevated interferon-stimulated gene transcription in peripheral blood mononuclear cells occurs in patients infected with genotype 1 but not genotype 3 hepatitis C virus

Hepatitis C virus (HCV) can be classified into seven distinct genotypes that are associated with differing pathologies and respond differently to antiviral therapy. In the UK, genotype 1 and 3 are present in approximately equal proportions. Chronic infection with HCV genotype 3 is associated with increased liver steatosis and reduced peripheral total cholesterol levels, which potentially influences peripheral immune responses. To understand these differences, we investigated host gene transcription in peripheral blood mononuclear cells by microarray and quantitative PCR in patients with genotype 1 (n = 22) or genotype 3 infection (n = 22) and matched healthy controls (n = 15). Enrichment of genes involved in immune response and inflammatory pathways were present in patients infected with HCV genotype 1; however, no differences in genes involved in lipid or cholesterol metabolism were detected. This genotype-specific induction of genes is unrelated to IL28B genotype or previous treatment failure. Our data support the hypothesis that genotype 1 infection drives a skewed Type I interferon response and provides a foundation for future investigations into the host–pathogen interactions that underlie the genotype-specific clinical outcomes of chronic HCV infection

Teaching models in the clinical years of medical education

Students are exposed to a range of teaching methods during the pre-clinical and clinical years of medical school. At Imperial College London, the pre-clinical years involve a predominantly lecture-based approach, with the aim of efficiently disseminating large volumes of knowledge to a large cohort. As clinical years approach, there is a swift move towards hospital-based teaching, where students have the independence to make the most of learning opportunities during placements. As learning objectives during medical studies, a corresponding change in teaching method is necessary. However, a sudden transition between teaching models or an overreliance on any one can be detrimental

Reduction of cogging torque of radial flux permanent magnet brushless DC motor by magnet shifting technique

  Introduction. In spite of many advantages of radial flux permanent magnet brushless DC motors it suffers from the distinct disadvantage of high cogging torque. The designer must emphasize to reduce the cogging torque during the design stage. This paper introduces magnet shifting technique to mitigate cogging torque of surface mounted radial flux brushless DC motor. Methodology. Initially 200 W, 1000 rpm surface mounted radial flux permanent magnet brushless DC motor is designed with symmetrical placement of permanent magnets with respect to each other on rotor core. Cogging torque profile of this initial motor is obtained by performing finite element modelling and analysis. Originality. This design has been improved by shifting the position of permanent magnets with respect to adjacent permanent magnets. The effect of magnet shifting on cogging torque has been analyzed by performing finite element analysis. Results. It has been examined that the peak to peak cogging torque is decreased from 1.1 N×m to 0.6 N×m with shifting of permanent magnets respectively.Вступ. Незважаючи на багато переваг безщіткових двигунів постійного струму з радіальним магнітним потоком, вони мають явний недолік, що полягає у високому крутному моменті зубчатої передачі. Проектувальник повинен зосередитись на зниженні крутного моменту зубчатої передачі на етапі проектування. У цій статті представлена методика зсуву магніту для зменшення крутного моменту зубчатої передачі безщіткового двигуна постійного струму з радіальним потоком, встановленого на поверхні. Методологія. Спочатку безщітковий двигун постійного струму з радіальним магнітним потоком потужністю 200 Вт, 1000 об/хв спроектований із симетричним розміщенням постійних магнітів відносно один одного на сердечнику ротора. Розподіл крутного моменту зубчатої передачі цього початкового двигуна отриманий шляхом аналізу методом скінчених елементів (МСЕ). Оригінальність. Ця конструкція була вдосконалена за рахунок зсуву положення постійних магнітів по відношенню до сусідніх постійних магнітів. Вплив зсуву магніту на крутний момент зубчатої передачі було проаналізовано за допомогою аналізу МСЕ. Результати. Досліджено, що піковий крутний  момент зубчатої передачі зменшився з 1,1 Н×м до 0,6 Н×м, відповідно, при зсуві постійних магнітів