Students Motivations For Voluntary Remedial Learning In High School

Most high schools offer remedial learning sessions to their students; however, very little is known about the perception of these activities, especially with regards to the students motivations. In order to gain insights into both topics, an exploratory study was conducted within a sample of 1388 high school students in the Province of Quebec (Canada). Participants were selected on the basis of their voluntary participation or non-participation in remedial learning sessions held at school. School motivation was measured with a questionnaire based on Deci and Ryans SDT (Self Determination Theory); perceptions were gathered and measured with open-ended and multiple choice items. Quantitative results indicated that participants of remedial learning sessions were more strongly motivated towards school. No significant relationships were found between attendance and grades, with similar proportions of high, average and below average participating and non-participating students; however, among participants, girls outnumbered boys by 2:1. Two main categories emerged from qualitative analyses: remedial learning can be seen as: a) an instrumental support linked to the subject matter; or b) a relational support which fosters better learning

Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis

Motivation and method: Small-molecule inhibitors targeting the adenosine triphosphate (ATP) binding pocket of the catalytic domain of protein kinases have potential to become drugs devoid of (major) side effects, particularly if they bind selectively. Here, the sequences of the 518 human kinases are first mapped onto the structural alignment of 116 kinases of known three-dimensional structure. The multiple structure alignment is then used to encode the known strategies for developing selective inhibitors into a fingerprint. Finally, a network analysis is used to partition the kinases into clusters according to similarity of their fingerprints, i.e. physico-chemical characteristics of the residues responsible for selective binding. Results: For each kinase the network analysis reveals the likelihood to find selective inhibitors targeting the ATP binding site. Systematic guidelines are proposed to develop selective inhibitors. Importantly, the network analysis suggests that the tyrosine kinase EphB4 has high selectivity potential, which is consistent with the selectivity profile of two novel EphB4 inhibitors. Contact: [email protected]; [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Optimization of inhibitors of the tyrosine kinase EphB4. 2. Cellular potency improvement and binding mode validation by X-ray crystallography

Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4

Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. Cellular Potency Improvement and Binding Mode Validation by X‑ray Crystallography

Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4

Discovery of a Novel Chemotype of Tyrosine Kinase Inhibitors by Fragment-Based Docking and Molecular Dynamics

We have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound <b>7</b>) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 μM to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 Å resolution