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

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.