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I have been busy in the lab working at the bench and training our new recruits to the Huntington’s disease research team! Welcome Jacob and Claudia! Using a technique called BioID, we have identified proteins which are proximal or nearby to the HTT protein in cells. To date, no published literature details the use of Read More …
Hello again. My apologies for the delay in posting – I’ve been busy with other projects lately. As a follow up to my previous post, we wanted to further confirm our EZH1 antibody and test it in a knockout line. To do this, we generated a CRISPR knockout of EZH1 in an AML cell line Read More …
In a previous post, I tested hit analogues and found compound XSR00035795a (Figure 1) had increased potency and ligand efficiency; however, compound XSR00035795a was also found to bind to HDAC6 Zf-UBD, so it was not selective towards USP5. Figure 1. XSR00035795a We hypothesized that it was possible to extend the aliphatic group on the carboxylic Read More …
Proteolysis Targeting Chimeras (PROTACs) are small molecules that induce the degradation of their target and have shown considerable promise as a novel therapeutic modality.1-3 PROTACs are heterobifunctional compounds containing one chemical moiety that binds to the target protein of interest and a chemical handle that binds to an E3 ubiquitin ligase (Figure 1). Recruitment of Read More …
It has now been almost 2 years since I set out to try and make fragments of the huntingtin protein which might be amenable to structural analysis with X-ray crystallography. X-ray crystallography is a fantastic method and allows us to see the molecules in very fine atomic detail which is important if we are to Read More …
In my last post, I mentioned I would be doing an internship at a biotech company in Montreal, Molecular Forecaster Inc as a part of a NSERC ChemNet CREATE grant. I’ve been in Montreal for about three weeks now and have had a chance to play around with the Forecaster software. I did preliminary docking Read More …
Update on meetings, manuscripts and mighty cool experiments…
In a previous post, I tested hit analogues against USP5 Zf-UBD using a SPR assay. Compound AE-641/11456811, now aptly re-named XSR00035795a (an SGC global ID- since our database infrastructure is finally re-vamped), had a binding affinity of approximately 60 µM. The addition of a methyl group on the carboxylic chain of the compound increased potency Read More …
Optimisation of HTT-HAP40 purification using heparin affinity chromatography
In a previous post, I described using hit expansion tools such as commercial substructure searches, docking, and free energy perturbation (FEP) simulations to explore the structure activity relationship (SAR) of the chemical series focused on the Zf-UBD of USP5. The first batch of commercially ordered compounds arrived just before the Christmas holidays. I decided to Read More …
