Therapeutic protein degradation by design?
The old problem and the new paradigm Classical small molecule drug paradigms generally involve intervention at a ligand protein binding ...
The last time I worked for Cresset I ended up being outsourced to a customer – but it was all part of the service! I’m delighted to be back at Cresset Discovery Services to work on a new set of customer projects. Here’s a brief overview of my computational chemistry journey so far.
I was introduced to computational chemistry when I stayed on at Warwick for a research MSc. The project was an SAR analysis of bell pepper odorants predicting the structural and electronic features that are important for olfactory recognition. My sponsor, Ernest Pollack, was getting very excited about proteins called GPCRs, which had just been identified as the receptors responsible for smell, and could possibly be the largest collection of proteins yet found. Meanwhile, I moved on to a PhD using quantum mechanics to investigate the Heck reaction.
In 2001 I joined Proteus (later Protherics, then Tularik), who had a history with Factor Xa and already had a licensing agreement with Lilly for LY517717 established. After the takeover by Tularik the focus moved onto kinases which were difficult for our in-house software to model accurately. It was here that, with help from Mick Knaggs, I moved back into ligand-based design. I started homology modeling to augment the range of targets available for the in-house structure-based design methods and to expand the range of target we could work on using ligand-based design tools.
I joined Sterix/Ipsen in 2004. Sterix had three areas of research: tubulin, hydroxysteroid dehydrogenase and dual aromatase-sulfatase inhibitors. Frustratingly, our work on these projects was limited to structure-based design, due to the fact that the group had made a large investment in the GOLD docking package from CCDC.
Upon moving to Peakdale Molecular in 2006 I worked on a range of diverse and interesting projects using a wide range of computational chemistry methods, including structure-based, ligand-based, ADMET predictions, homology modeling, molecular dynamics, quantum mechanics, cheminformatics, bioinformatics, library design, diversity and similarity analysis. The diversity of the projects meant I quickly learned to adapt to customer priorities, selecting the most appropriate method for the best possible modeling solution, whilst maintaining value for money.
It was here that I first used Cresset software. Torch (then FieldAlign) and Forge (then FieldTemplater) provided intuitive and visually informative methods for analyzing molecules which were understandable to our customers. These applications offered very useful methods of treating molecules which were different from other approaches I’d used before; both tools gave a more insightful understanding of ligand similarities and a deeper understanding of the features driving activity across a wide range of chemotypes and targets.
Redx were working closely with Cresset, but were unsure how much support they would need, so in 2013 I took on the joint role of computational chemist at Redx and application scientist at Cresset.
Redx had fully functional medicinal chemistry projects in anti-infectives, oncology and crop protection, with large repositories of data. The established computational methods from Cresset Discovery Services showed the potential of computational chemistry and was the reason for Redx wanting to bring computational chemistry in-house. I provided the computational chemistry component and established a close working relationship with the medicinal chemistry teams.
Spark, Cresset’s scaffold hopping and R-group exploration application was integral to the development of a patent busting portfolio. As the company matured, Spark was used for backup series generation and to prevent the same patent busting approach to be applied to our own patents.
As an application scientist at Cresset, I carried out a very preliminary investigation of protein fields to determine whether we could transfer the Cresset methodology from ligands to proteins. It’s very gratifying to see the evolution of this early work brought to market in Flare, which provides fresh insights into structure-based design by integrating cutting edge approaches in an accessible and flexible user interface.
I joined Redx full time when it became clear that they needed more computational support. Working closely with Cresset software support, synthetic chemists were trained on Forge, a powerful ligand-focused workbench for SAR and design, and were encouraged to undertake general computational chemistry project related tasks. This freed up my time to provide more in-depth investigations to several key problems on projects.
A significant success was a compound that was sold to LOXO Oncology for $40 million. The computational work for this project was originally outsourced to Cresset Discovery Services. The compound was developed in 5 years and is a testament to the quality science undertaken at Redx.
In fact, the Redx CEO at the time was so impressed with the contribution of Cresset Discovery Services that he wrote:
“Cresset is a valuable partner in our drug discovery programs. Their deep knowledge of computational chemistry and its application to drug discovery is enabling us to progress multiple projects across a wide range of target classes very quickly and cost-effectively.
“Cresset has consistently delivered insightful support to our drug discovery efforts. In our experience, their knowledge, responsiveness and collaborative approach have set them apart from their competitors.”
Dr Neil Murray, CEO, Redx Pharma, UK
I was delighted when I heard that Cresset Discovery Services was looking for a computational chemist to join the team. I’m very pleased to be back to working on a wide range of challenges on varied customer projects and putting my skills to use in the real world of modeling.
Contact us for a free confidential discussion to see how Cresset Discovery Services can work alongside your chemists to solve problems, provide fresh ideas, remove roadblocks and add direction and insight to you project. If you’re based near Alderley Park and would like to meet for a confidential chat, get in touch as I’m based at the BioHub part-time.