With a successful vaccine roll out and boasters jabs in the UK, the first full in person conferences have been taking place again. In the last two weeks I have attended two; of course, the virus does know about conferences so I was still wearing a face mask, even though the restrictions have been lifted. Face to face conversations (no hand shaking, and I think we should stay that way – who wants any cold or illness) were nearly all about the pandemic and the war in Ukraine. On top of the pointless horror of the war, we have all become acutely aware that much of our drug discovery efforts have become dependent on chemistry performed in Ukraine and Russia. Building blocks, libraries and compound synthesis from Enamine have been a critical part of the Covid Moonshot effort (see other articles). Nonetheless it was good to see people again.

On a positive note, here are a few highlights from the two conferences I attended:

SMR SCI Experimental and in silico approaches to target selection and tractability for drug discovery
Monday 21st March
The Francis Crick Institute, London

This conference focussed on finding new targets and then, once found, turning these undruggable targets into druggable. I am struck at how much this field has progressed and it is clear that no single technique fits the bill. This is not a surprise to any of us in the med chem field, perhaps an AI system that helps us pick the right technique first time would be good idea? Very positively the industry has pointed the ship at attacking complex protein interactions. The talk from Dr. Lyn Jones (Targeted covalent inhibitors and molecular superglues) found small molecule ‘inhibitors / modulators’ of a tri-complex of proteins. A fairly new term in the industry is ‘molecular glue’, this looks like a good example. As I understand the molecule holds the three proteins together and stopped them entering the active state. If you asked me to ‘design’ a ‘molecular glue’ I would have no idea how to do it – currently I think in this game you will be pleased to have some chemical matter to start with, no matter ‘how’ it works – that would be a retrospective piece of analysis.

I thought the best talk of the day was:

Adapting to a changing portfolio landscape: an industry perspective of experimental approaches to assess target tractability and hit finding
Ian Storer, AZ, Cambridge, UK

Ian covered AZ efforts in new modalities of drug finding, which I think could be everything except running a high-through put screening. On another personally note, and this talk supports it, I think high-through put screening is dead. To be more precise, the days of screening millions of compounds (one per well) is over. It is expensive, time consuming and it only find hits for target classes that you already know about. I will sell my shares in any large pharma that is still doing this in 5 years’ time, and continuing to do this ensures any new drug will be fifth or worst to the clinic. AZ have embraced combined techniques of fragment screening, black box, high content screening, DNA encoded libraries and the likes of protein degradation, in work flows to find new hit matter. The most interesting part of the talk was the use of 19F NMR for affinity screening with fluorine containing fragments mixed in cocktails of up to ninety (yes 90). This enabled a fragment screen to be performed in a couple of days.

Fragments 2022

Monday 28th / Tuesday 29th March

Churchill College Cambridge

A week later I attended Fragments which overlapped with ‘target selection and tractability’ conference to some degree. Throughout the two days the talks were excellent and the venue was full of exhibitors, keen to tell you how they had constructed their fragment library.

For me the highlight of the conference was:

Fragments: Impact, Lessons and What’s Next?

Roderick Hubbard, University of York and Vernalis

Working with HitGen, a DNA tagged library of fragments was screened using their technology with the added step of illuminating the mixture with UV light. Each fragment is actually joined to the DNA tag by a flexible linked of varying length with a central diazo group. The UV light activates the diazo group, generating a carbene which binds to the protein. This step converts a weakly binding fragment into a covalently bound compound and effectively binds the DNA tag to the protein. HitGen’s methods for separation and de-convulsion yields the list of fragment hits.  At first this seems like the opposite of giant DNA encoded libraries, but a key part is the variation in diazo linker lengths required for optimal placement of transient carbene. So, with 1000 fragment multiplied by 2 combinations of linker length the library size grows, even so it is still smaller than the ‘usual’ billions of molecules in a DEL.