Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective long-term treatments. The retrotransposon-derived protein PEG10, essential for placental development, has recently been implicated in ALS through its aggregation in motor neurons. This aggregation, linked to Ubiquilin-2 dysfunction, promotes PEG10 self-cleavage via its own aspartic protease domain, producing cleavage fragments that cause harmful transcriptional changes in neurons. Therefore, inhibiting PEG10 self-cleavage represents a promising therapeutic strategy. We perform the first-ever atomistic molecular dynamics (MD) simulations of the PEG10 aspartic protease domain, and subsequently use a combination of small molecule docking and MD to screen existing inhibitors—originally developed against other aspartic proteases such as HIV protease—for their ability to bind PEG10. These interactions are analyzed through binding free energy calculations, occupancy profiles, and dynamic behavior within the active site. Our simulations reveal key insights into PEG10’s structural dynamics, including the flexible flaps that regulate ligand accessibility. We identify small molecules that engage the PEG10 active site and define the physicochemical features that govern these interactions. These findings provide fundamental mechanistic insights for the rational design of PEG10-targeted inhibitors and open new avenues for therapeutic development in ALS.
