Bifunctional degraders have recently emerged as a new pharmaceutical modality. In fact, earlier this year the first bifunctional degrader anticancer drug ARV-110 hit the clinic. Many Pharma and Biotech companies are investing in this emerging modality. However, targeted protein degradation is a complex multi-step process that presents an increase in the level of technical challenges and complexity. One of the key steps is the formation of the ternary complex between the target, degrader and E3 ubiquitin ligase, which results in the degradation of the target. Therefore, there is a need for robust computational methods to predict relevant ternary complexes that can aid in the rational design of bifunctional degraders.<br/>We have developed several workflows for bifunctional degrader modeling, which include conformational sampling of the degrader, determination of the degrader exit vectors and prediction of possible ternary complexes. Based on preliminary validation using available crystal structures, the results are encouraging and show that MD in combination with protein-protein docking are powerful tools to tackle this challenging problem.<br/>

Development of workflows for bifunctional degrader modeling

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.