Ternary Complex Modeling, Induced Fit Docking and Molecular Dynamics Simulations as a Successful Approach for the...

Proteolysis targeting chimeras (PROTACs) have proven to be a novel approach for the degradation of disease-causing proteins in drug discovery. One of the E3 ligases for which efficient PROTACs have been described is the Von Hippel-Lindau factor (VHL). However, the development of PROTACs has so far often relied on a minimum of computational tools, so that it is mostly based on a trial-and-error process. Therefore, there is a great need for resource- and time-efficient structure-based or computational approaches to streamline PROTAC design. In this study, we present a combined computational approach that integrates static ternary complex formation, induced-fit docking, and molecular dynamics (MD) simulations. Our methodology was tested using four experimentally derived ternary complex structures of VHL PROTACs, reported for BRD4, SMARCA2, FAK, and WEE1. In addition, we applied the validated approach to model a recently in-house developed FLT3-targeted PROTAC (MA49). The results show that static ternary models generated with a protein-protein docking method implemented in the software MOE have a high predictive power for reproducing the experimental 3D structures. The induced-fit docking of different active PROTACs to their respective models showed the reliability of this model for the development of new VHL-mediated degraders. In particular, the induced-fit docking was sensitive to structural changes in the PROTACs, as evidenced by the failed binding modes of the PROTAC negative controls. Furthermore, MD simulations confirmed the stability of the generated complexes and emphasized the importance of dynamic studies for understanding the relationship between PROTAC structure and function.