PROTAC small molecule design project

We’re happy to officially announce an ambitious new scientific project making use of the updated Small Molecule Design tool

Controlled protein degradation

Your cells need to constantly recycle old proteins. One way they do this is by tagging unneeded proteins with a specific signal molecule (ubiquitin) which sends them to the proteasome where they are cut up into individual amino acids. The ubiquitin tag itself is sufficient to cause the protein to be degraded, so the cell has a number of complex signalling pathways which normally control which proteins get tagged at what time. (This is the E1/E2/E3 enzyme cascade.)

Proteolysis targeting chimeras (PROTACs) are an exciting new approach to hook into that system, to promote degradation of proteins which wouldn’t otherwise be degraded. They work by having one end which binds to the protein to be destroyed, and another end which binds to an E3 ubiquitin ligase. Simply by binding to both proteins and bringing them together, a PROTAC causes the E3 ubiquitin ligase to tag the nearby target protein with ubiquitin and thus send it for degradation. The beauty of the system is that the portion of the molecule that binds the target and the portion which binds the E3 ligase are completely independent, connected by a generic linker. This makes it much easier to develop the parts separately and then combine them.

Not only are PROTACs an exciting possibility for developing new drugs, they’re an excellent research tool to figure out how proteins work in cells and organisms. Current approaches for gene function research rely heavily on “knockout” studies in model organisms, where the gene is removed entirely. This approach has limitations in that you can’t control when and where the protein is removed (it’s removed from everywhere always). It also requires difficult and costly genetic manipulation of the organism. PROTACs allow you to control the timing of protein removal by when you apply the drug, and by which E3 ligase you target. And you can do this in unmodified “wildtype” cells and organisms.

Specificity needed

Currently, we’re somewhat limited by the number of small molecules which can target E3 ubiquitin ligase. Humans have over 500 different E3 ligase genes, each with their own expression profile and localization. We have comparatively fewer small molecules which can bind to the E3 ligases, and the ones we do have aren’t necessarily great for drug purposes. (Thalidomide is a popular choice for research purposes.) This limits the control we have over when and where the PROTACs work.

We hope you can change that! Using the small molecule design tool, you can make small molecules which bind to an E3 ligase, and thus can be a potential base for future PROTACs. The hope is that by developing a library of compounds which bind to different E3 ligases with different specificities, we’ll develop an arsenal of PROTAC-halves which can be used by future researchers. They’ll only have to worry about finding a binder to their protein of interest, and can then take an E3 ligase binder “off the shelf” and “simply” connect the two. With a library of E3 ligase binders, they can use the same protein of interest binder and target different E3 ligase binders, depending on their purposes.

The initial E3 ubiquitin ligase we targeted was the von Hippel-Lindau tumor suppressor protein (VHL). VHL has already been shown to be useful as the E3 target of PROTACs, and there’s existing publications showing what makes a good VHL binder. However, the existing binders are not particularly “drug like”, so we thought there was plenty of room for Foldit players to improve the state-of-the-art. To get an update on the status of VHL designs, check out the most recent VHL Ligand Design Blog Post

Compounds will be tested - will yours?

We’ve teamed up with a major pharmaceutical company - Boehringer Ingelheim (BI) - for this project. They approached us, wondering how they could support the small molecule design efforts in Foldit. BI has a history of supporting open science, for example creating opnMe to share BI-generated molecules. They are excited about the possibilities citizen science has in supporting open research in small molecule drug design, and think Foldit is a great way to achieve this.

Boehringer Ingelheim has committed to help evaluate and test the molecules which Foldit players have designed. Molecules you create in Foldit will be passed on to the team at BI, who will evaluate them based on the same criteria used for their own internal small molecule development. Compounds which pass the test will then be synthesized and tested for binding by BI. They have also volunteered to try to determine the crystal structure of successful protein-small molecule complexes, so we can better determine how well the Foldit design matches the actual experimental structure.

All participants and game sponsors of current and future small molecule design games commit to complying with the Foldit Terms of Service including those pertaining to intellectual property.

All compounds created as part of the collaboration puzzles will be made publicly available. Experimental results from testing the molecules will also be released publicly.

( Posted by  rmoretti 51 415  |  Wed, 10/20/2021 - 21:11  |  0 comments )
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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, Boehringer Ingelheim, RosettaCommons