Additional file 1 of GATE: an efficient procedure in study of pleiotropic genetic associations

GATE: an efficient procedure in study of pleiotropic genetic associations. (PDF 317 kb

Kinase selectivity screening.

<p>Compounds were screened in one of two kinase panels at a concentration of 10 µM. The degree of inhibition of each kinase is indicated by shading as follows: white <29% inhibition, light grey 30-49% inhibition, dark grey 50-69% inhibition, black >70% inhibition. Key to compounds: (1) 0181276, (2) CE-160042, (3) 0180532, (4) PF-4903528, (5) PF-4936572, (6) PF-4995633, (7) AG-24290, (8) PF-4279731, (9) CE-317112, (10) PF-1242377, (11) PF-744923, (12) PF-2368935, (13) PF-956933. NT  =  not tested.</p

GSK-3 Enzyme, Antiparasitic and cytotoxicity testing (values in µM).

<p>Values are a mean of at least 2 replicates. NT  =  not tested due to limited compound availability.</p><p>*Due to limited compound availability, these compounds were only tested at a single concentration of 1 µM and showed >50% inhibition at this concentration.</p

Modelling of the binding-site residues with putative inhibitors.

<p>Compounds (orange) docked into the catalytic domain of the crystal structure of <i>Hs</i>GSK3 beta in their binding modes. A: CE-317112 shows preference for <i>Hs</i>GSK-3 beta. B: PF-4903528 shows preference for <i>Tbru</i>GSK-3 short. The residues that differ between human and <i>Tbru</i>GSK-3 short are shown in magenta, with only L132M (top centre of the image) directly lining the pocket. Images were created using the Pfizer molecule-modelling package MoViT.</p

Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening Platform

Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure–activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC₅₀ > 8 against Abl kinase  both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases