Results from soaking follow-up compounds into preformed HAO1 crystals

In my last post, I told you I had soaked my follow-up compounds into HAO1 crystals to start developing structural explanations of how these compounds work. So far I have analysed four interesting protein-compound structures: 2 at the active site, 1 at the gating loop and 1 at the oligomeric interface. Full experimental details can Read More …

Collecting HAO1 crystal structures with follow-up compounds based on fragment hits

A belated Happy New Year everyone!  It has been a good while since my last post so I wanted to update you on what I have been spending 2019 on so far. After identifying some really promising follow-up compounds in my activity assay, the next step was to find out how they bind to HAO1, Read More …

Synthesis and testing of follow up compounds based on HAO1 fragment 6, bound at the tetramer interface.

Hello again! A few posts ago (here), I presented one fragment bound at the interface between two subunits of the HAO1 tetramer (figure 1 will refresh your memory). Our idea to optimize this fragment into an inhibitor would be to make it bigger so that it disrupts the HAO1 tetramer. I would expect this to Read More …

Screening follow up compounds from active site and gating loop HAO1 fragment hits

In my previous post, I confirmed that the two active site fragments (fragments 1 and 2) and the gating loop fragment (fragment 5) bind to and inhibit HAO1 in solution. Next, I chose some larger compounds to test by entering each fragment hit structure into a search engine (emolecules.com) to look for commercially available compounds Read More …

Characterisation of HAO1 fragment hits in solution

In my previous post, I described four promising fragments bound to HAO1 structures. Specifically, I described two key areas of HAO1 – the gating loop and active site Trp110 – where fragments 1, 2 and 5 bind. I also described fragment 6 at the subunit interface of HAO1, away from the active site. After analysis Read More …

Analysis of fragments that bind to HAO1

In my previous post, I introduced our fragment screening results on HAO1. Specifically, I told you that we identified five promising fragment hits, from a little over 400 collected structures, clustering to three biologically relevant sites: the active site (fragments 1 and 2), the gating loop (fragment 5) and the subunit interface (fragments 6 and Read More …

Speaking at the annual conference of the Society for the Study of Inborn Errors of Metabolism (SSIEM)

Hello again! This week I am in sunny, sunny Athens attending the SSIEM annual conference that brings together renowned experts in inborn errors of metabolism from around the world to present their latest pre-clinical and clinical research. I was fortunate enough to receive a generous travel grant from the SSIEM to give a talk this Read More …

Identifying fragments that bind to HAO1 by x-ray crystallography

In this post, I would like to share my recent work on HAO1 fragment screening by crystallography, as a means to identify inhibitor starting points. So why fragment screening by x-ray crystallography? Well there are two components to my method of choice: Fragments instead of complex compounds provide good starting chemistry Fragments are less than Read More …

Project overview: Inhibition of HAO1 to treat primary hyperoxaluria type 1

Hello everybody! I am Sabrina, a third year DPhil student in Wyatt Yue’s lab at the SGC University of Oxford, co-supervised by Paul Brennan. I am fascinated by how a single base change in an enzyme-coding gene can lead to a diverse group of symptoms and how the severity of such diseases can be reduced Read More …