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 ...
In the search for a compound that is efficacious, well tolerated and novel most drug discovery projects hit a hurdle or two. In most cases the problem is not in the activity of the lead compound, but in its physicochemical, ADMET or intellectual properties. Sometimes this can be ameliorated by small changes to the structure, but in most cases this is not sufficient. In this case the best solution is usually to move the project into new areas of chemistry towards compounds that have a better ADMET profile, better IP or better properties. The trick is to do this without losing all of the hard-won knowledge on SAR around the existing series and especially not losing the hard-won activity of the lead.
A common approach is to ‘scaffold-hop’ – change the ‘core’ or ‘scaffold’ of an active molecule while retaining the attached R groups as much as possible. In the ideal case the resulting molecule will have a biological activity very similar to the original, but its different core leads to a new ADMET and IP profile, solving the problems with the original compound. Since Cresset’s field similarity approach describes the binding preferences of a molecule, what we want to find is an alternative core that preserves the field pattern of the original.
Cresset consultants have extensive experience in applying this technique to help clients to kick-start a new project or ‘un-stick’ an existing one. We use our synthetic and computational experience together with our software to analyze your data and suggest new chemical series that will take you in the direction that you want to go.
We may start by developing 3D templates or pharmacophores, or developing models of your SAR using Activity Miner or FieldTemplater. We would then go on to use Spark to suggest novel core replacements that we refine in Forge. Alternatively, we may work closely with your synthetic chemists to define all the possible scaffolds that can be introduced into your molecules. We then use this information in Spark, Forge or BlazeGPU to find the best possible option. Either way, we get your project moving in the right direction, delivering the best possible combination of chemical and biological properties. Throughout this process we work closely with you to ensure that our suggestions fit your project goals and synthetic capabilities.
In the pharmaceutical industry, confidentiality is of fundamental importance to our clients. For this reason, our most impressive work is usually not publishable, so we carry out retrospective analyzes of published projects in order to provide examples of our capabilities.
In spring 2013, Tim Cheeseright, Cresset’s Director of Products, presented a detailed study on the use of Spark for scaffold hopping from the core of Sildenafil, in a comparison with a published technique from Pfizer. He showed that Spark not only found all of the scaffolds identified by the Pfizer team, but located additional known active cores while only using a fraction of the computation time.
At this year’s Cresset North American user group meeting the independent medicinal chemistry consultant Alfred Ajami gave a presentation describing the use of Spark to retrospectively analysze two case studies from the bioisosteric replacement literature and to evaluate its performance in a number of projects that he has been involved with. You can see the full presentation ‘Pharmaceutical hunts with Spark: case studies from the literature and current campaigns to develop immunokinase inhibitors’, Alfred M Ajami, DCAM Pharma Inc.
These studies show the power of the Cresset methods to free your drug discovery program from being stuck in a dead-end series. contact us for more information about how Cresset Consultants can help to kick-start or un-stick your project.