Computational prediction and molecular mechanism of γ-secretase modulators

Selective control over Aβ production via γ-secretase modulators (GSM) is a promising strategy for treating Alzheimer's disease, yet the specific binding sites and mechanism of action GSMs remain unknown. Using recent cryo-electron microscopy structures substrate-bound we used two distinct methods to identify four potential pyridopyrazine-1,6-dione GSMs. We demonstrate site 4 formed between PS1-TM2, PS1-TM5 APP-C83-TM, with experimental activity data correlating significantly (95% confidence) our computed binding-affinities this site. Charged protonated may display higher affinities because π-cation interaction polar residue Tyr115 PS1-NTF. Surprisingly, pIC50 these compounds largely described (R2 > 0.4 all these) by molecular size, hydrophobicity, polarizability. thus believe that have identified primary modulator in compounds, as well strong descriptors GSM potency. Our results are consistent FIST model suggest work ways: The affinity itself contributes stability ternary enzyme-modulator-substrate complex (tight grabbing), preventing early release substrate increasing trimming shorter, innocent peptides. At same time, drug polarizability stabilize more compact semi-open state open PS1 state, make cleavage precise complete.