Assessing the Stability of Molecular Glues with Weighted Ensemble Simulations

Abstract

Targeted protein degradation is an emerging approach that utilizes cellular degradation pathways to inhibit a target protein. Small molecules such as molecular glues or PROTACs can be used to mediate the formation of a ternary complex with an E3 ligase and the target protein, which can dramatically enhance the degradation process. This approach is promising for cancer therapy, where degradation of oncogenic proteins can lead to cancer cell toxicity. To design new molecular glues, it is important to develop methods that predict how well a given molecule stabilizes a protein-protein interaction. However, conventional molecular dynamics simulations face challenges in capturing the long-timescale binding and unbinding events that would be used to evaluate this stabilization. In this study, we developed a strategy that allows us to evaluate the stability of protein-protein interactions in the presence of a glue molecule using weighted ensemble simulations in combination with weakened protein-protein interactions. Using this strategy, we generated unbinding trajectories of the DCAF15-RBM39 system with small molecules E7820, Indisulam, and several other Indisulam analogs. We were able to observe distinctly different behaviors between systems with different glues, which was in agreement with their reported EC50 values. We believe this approach could aid drug discovery efforts by expanding the set of druggable targets and improving the success rate of molecular glue development.