Figures & data
Figure 1. Chemical structures of GABA, Vigabatrin, rigid GABA analogues (1 and 2) and the newly designed bicyclic compounds 3 and 4, described in this work.
Figure 2. Absorption spectra of GABA-AT before (continuous line) and after (dashed line) 30 min treatment with 1 mM (+)-3 at 20 °C. Inset: time- and concentration-dependent inactivation of GABA-AT at 25 °C by (+)-3.
Table 1. Percentage of inhibition at the screening concentration (1 mM) after 1 d at 4 °C.
Scheme 1. Proposed reaction mechanism. To simplify the scheme, only one representative compound, i.e. (+)-3, is shown.
Scheme 2. Reagents and conditions: (a) NaHCO3, EtOAc; (b) preparative HPLC separation; (c) CH3SO3H, H2O, THF, Δ.
Figure 3. Superposition of co-crystallized Vigabatrin-PLP with proposed binding mode of (+)-3 (dark gray) and (+)-4 (light gray) as provided by Plants. H-bonds are shown as dotted lines in light gray for Vigabatrin-PLP, in dark gray for adduct 8. Lys329, involved in nucleophilic attack, is reported in stick. Distances between ɛ-amino group of Lys329 and the electrophilic center of Vigabatrin and adduct 8 are 2.3 and 2.9 Å, respectively. The main residues involved in binding are also reported.
Figure 4. Proposed classical (dark gray) and covalent (light gray) docking binding mode of (+)-3 (left) and (−)-3 (right). H-bonds observed for Plants docking poses are shown as dark dotted lines, whereas for covalent docking poses obtained by PrimeCitation27 are shown as light dotted lines.
