Fig. 4: Molecule binding to αS fibrils.
From: Discovery of potent inhibitors of α-synuclein aggregation using structure-based iterative learning
a, A schematic representation of small molecule binding to the target binding pocket on the αS fibril. b, SPR response curves for different concentrations of I4.05, at pH 4.8 and pH 8, binding to αS fibrils generated by a seeded assay, with the corresponding molecular structure. Raw data (points) and the corresponding fits (solid lines) for each molecule concentration are shown (n = 2 replicates). Response units (RU) are shown on the y-axes. The αS fibrils were immobilized at a concentration of 2,000 pg mm−2 on a CM5 Cytivia chip. The fits correspond to a 1:1 kinetic binding model, which yielded a KD of 68 nM (ka = 1.936 ± 0.007 × 105 M−1 s−1, kd = 1.315 ± 0.003 × 10−2 s−1) at pH 4.8 and 13 nM at pH 8 (ka = 5.879 ± 0.024 × 105 M−1 s−1, kd = 0.781 ± 0.002 × 10−2 s−1). Error: standard error of the mean (s.e.m.). c, SPR response curves for different concentrations of Anle-138b. Raw data (points) for each molecule concentration are shown (n = 2 replicates). Accurate fits at pH 4.8 could not be obtained. At pH 8 a 1:1 kinetic binding model yielded an approximate KD of 8.1 μM (ka = 0.0359 ± 0.0005 × 105 M−1 s−1, kd = 2.90 ± 0.02 × 10−2 s−1). Error: s.e.m. d, Seeded kinetics (40 nM seed, n = 2 replicates; central measure, mean; error, standard deviation) and SPR response curves (n = 2 replicates) for 2 μM Aβ42 in the presence of 1% DMSO or different concentrations of I4.05. I4.05 is unable to effectively inhibit Aβ42 secondary nucleation or bind to Aβ42 fibrils. The Aβ42 fibrils were immobilized at a concentration of 2,000 pg mm−2 on a CM5 Cytivia chip.
