DISCUSSION

Table 1 shows the main interactions and the pIC₅₀ for each FTase-inhibitor complex. In Table 2 the aminoacidic residues involved in the ternary complex FTase - HRAS-1 - FPP are mentioned. With the exception of Lys-164A, which represents the only common interaction point, the residues involved in the complex formation are different, because the substrates bind at two distinct. In the (S)-FPOH complex (see Table 1), the inhibitor is not coordinated with the zinc ion although the (S)-FPOH is placed at the same site of FPP. The reason of this behaviour is the presence of the hydroxyl group of (S)-FPOH; this OH group has an unfavourable effect on the interaction. With the exception of SCH-44342, the other inhibitors coordinate the zinc.
The inhibitors table (Table 1) shows that Arg-291B, His-248B and Tyr-361B are the main aminoacidic residues involved in the stabilization of the complex. When the orientations of each FTase antagonist and those of the natural ligands are compared, one can observe that the inhibitors studied can be classified into three groups according to the interaction site:

• (S)-FPOH, like FPP, interacts with positively charged groups around the zinc ion (Lys-294B and Arg-291B).
• SCH-44342 and BZA-2B , like H-RAS, mainly interact with aromatic residues (Tyr-361B and His-248B).
• Zaragozic acid and Fusidienol fit both into the FPP and H-RAS sites. This peculiarity may explain the greater activity of Zaragozic acid with respect to FPOH or SCH-44342.

BZA-2B has additional interactions with aminoacidic groups (Asp-359B and His-362B) that are not involved in the formation of any of the other complexes, including the FTase-HRAS-FPP complex. Thus, these results provide qualitatively acceptable hints for an interpretation of the
different behaviour of ligands vs. the FTase.

Table 1 - Main interactions and pIC₅₀ of FTase-inhibitor complexes.

ZARA = zaragozic acid, DESME = 10'-desmethoxystreptonigrin, FUSID = fusidienol

Table 2 - Main interactions of FTase - H-RAS-1 - FPP complex.