Figure 2.

Depending on the substitution pattern, the aminobenzimidazole scaffold adopts three different binding modes. Crystal structures of the inhibitors are shown as follows:¹³ a) With only a small substitution in the 6-position, the inhibitor forms direct hydrogen bonds with the phosphate group of the co-factor NADP⁺. b) The unsubstituted scaffold forms water-mediated hydrogen bonds (red spheres) with the phosphate group of NADP⁺. c) When the scaffold is substituted at N1, the compound binds in an area of the binding site that is perpendicular to the canonical binding site.¹³ d) Hydrophobic pockets accessible by substitution of compound 11. The surfaces of the pockets for substitutions at the 7- and 4-positions of 11 are coloured yellow and green, respectively. e) X-ray crystal structure of compound 32 (shown in magenta) showing use of the 7’ hydrophobic pocket and the edge–face interaction of the 7-phenyl group with Trp221.