Docking results between curcumin, melatonin and ThT with several Aβ_1–42 conformers.

<p>The methodology to obtain the complex is the same as mentioned above for the docking studies with the selected compounds. ΔG values were obtained through docking studies of the ligands with <b>Aβ-α</b> (circles), <b>Aβ-RC</b> (rhombuses) and <b>Aβ-β</b> (squares) (A). The binding modes of curcumin, melatonin and ThT on <b>Aβ-α</b>, <b>Aβ-RC</b>, and <b>Aβ-β</b> (B).</p

Spatial distribution of SOMO on Aβ-α.

<p>The illustration is based on the mapping of 0.032 isovalues and values onto a total electron density surface contoured at 0.0004 e/au3, which was based on AM1 semi-empirical calculations. The interaction between the LUMOs of compounds 5 and 8 and the SOMO of <b>Aβ-α</b>, in eV (A); <b>Aβ-α</b>–compound 5 complex SOMO (B); and <b>Aβ-α</b>–compound 8 complex SOMO (C) are shown. A map of the electrostatic potentials showing the most positive potential (deepest blue color) and the most negative potential (deepest red color) plotted on a surface with constant electron density (0.02 e/au3). MEP for compound 5 after docking studies with <b>Aβ-α</b> (D); MEP for compound 5 after docking studies with <b>Aβ-β</b> (E); MEP for compound 8 after docking studies with <b>Aβ-α</b> (F); and MEP for compound 8 after docking studies with <b>Aβ-β</b> (G).</p

Proportions of Aβ_1–42 secondary structures in the absence or presence of 100 μM of the selected compounds.

<p>Proportions of Aβ_1–42 secondary structures in the absence or presence of 100 μM of the selected compounds.</p

AFM analysis after incubating 50 μM Aβ_1–42 alone or in the presence of the selected compounds at 100 μM after 24 h (A to E) or different incubation times (F and G).

<p>Aβ_{<b>1–42</b>} alone (A); Aβ_{<b>1–42</b>} and compound 5 (B); Aβ_{<b>1–42</b>} and compound 8 (C); Aβ_{<b>1–42</b>} and compound 14 (D); Aβ_{<b>1–42</b>} and compound 19 (E). Samples obtained at different incubation times for Aβ_{<b>1–42</b>} alone (F) or with compound 5 (G). Aβ_{<b>1–42</b>} (50 μM in MilliQ water) was incubated at 37°C in a quartz cell in the presence or absence of compounds 5, 8, 14 and 19 (100 μM) and stirred at 250 rpm for 24 h.</p

Docking results for the selected compounds with several Aβ_1–42 conformers.

<p>ΔG values were obtained through docking studies of the ligands with <b>Aβ-α</b> (circles), <b>Aβ-RC</b> (rhombuses) and <b>Aβ-β</b> (squares) (A). The binding modes of compounds 5, 8, 14, 21 and 26 on <b>Aβ-α</b>, <b>Aβ-RC</b>, and <b>Aβ-β</b> (B).</p

Comparison of LUMO, HOMO and SOMO (eV) and the electronic energies of the amino acid residues and compounds.

<p><b>(α)</b> After docking studies with <b>Aβ-α</b></p><p><b>(RC)</b> After docking studies with <b>Aβ-RC</b></p><p><b>(β)</b> After docking studies with <b>Aβ-β</b></p><p>Comparison of LUMO, HOMO and SOMO (eV) and the electronic energies of the amino acid residues and compounds.</p

Chemical structures of the inhibitors of Aβ_1–42 fibrillization.

<p>The majority of the compounds shared the presence of amines and/or aromatic rings.</p

Proposed Aβ-α pharmacophore based on the studies with compound 5.

<p>Schematic representation of the polar and nonpolar interactions that favor the interactions with <b>Aβ-α</b> (A); distances between principal chemical groups, the protonated amine (N⁺), the aromatic ring (Ar), and Alkyl substituent (<i>Tert-B</i>) (B). The main interactions involved in the recognition of compound 5 are electrostatic interactions with Glu22 and Asp23, π-π with Phe19 and Phe20 and hydrophobic interactions with Leu17.</p

Chemical structures of the selected compounds used as possible Aβ_1–42 oligomerization inhibitors.

<p>All of the compounds selected contained an amine and/or aromatic ring in their structure. However, not all of the compounds could acquire a positive charge at physiological pH. The compounds are shown with their protonation states based on their pKas.</p