PROTAC-Mediated Ternary Complex Stability with Ricin Toxin A: A Computational Perspective

Abstract

Ricin is a potent toxin present in the seeds of the castor plant (Ricinus communis), which is widely distributed in tropical regions. To date, there are no approved antidotes or vaccines against ricin poisoning. Reported inhibitors have not yet achieved sufficient affinity, and vaccine candidates have shown limited efficacy, highlighting the need to explore alternative strategies for RTA neutralization. In this work, we performed a computational study to investigate the potential of using PROTACs (proteolysis-targeting chimeras) to induce the ubiquitination and subsequent proteasomal degradation of ricin. Specifically, we assessed the stability of RTA, the catalytic subunit of ricin, in complex with the E3 ligases VHL and CRBN, both widely employed in the PROTAC design. Several PROTAC candidates with distinct linkers were evaluated to identify linkers with greater potential to mediate the stable ternary complex formation between RTA and the ligases. Molecular docking and molecular dynamics simulations revealed three promising PROTACs, one targeting CRBN and two targeting VHL, as potential candidates for further in vitro validation. Overall, this study introduces PROTAC-mediated degradation as a novel and unexplored therapeutic strategy against ricin intoxication, laying the groundwork for future experimental investigations.