Computational and Conformational Evaluation of FTase Alternative Substrates:  Insight into a Novel Enzyme Binding Pocket

• Published in: Journal of chemical information and modeling Vol. 45; no. 4; pp. 1047 - 1052
• Main Authors: Henriksen, Brian S, Zahn, Todd J, Evanseck, Jeffrey D, Firestine, Steven M, Gibbs, Richard A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.07.2005
• Subjects: Binding Sites; Computer Simulation; Enzymes; Farnesyltranstransferase - antagonists & inhibitors; Farnesyltranstransferase - chemistry; Farnesyltranstransferase - metabolism; Molecular Structure; Pharmaceuticals; Polyisoprenyl Phosphates - chemistry; Polyisoprenyl Phosphates - pharmacology; Protein Binding; Protein Conformation; Sesquiterpenes; Substrate Specificity
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci0496550

Protein farnesyltransferase (FTase) is an important anticancer drug target. In an effort to develop isoprenoid diphosphate-based FTase inhibitors, striking variations have been observed in the ability of conservatively modified analogues to bind to the enzyme. For example, 2Z-GGPP is an alternative substrate with high binding affinity, while GGPP is not an alternative substrate. Using the availability of high-resolution FTase crystal structures, we have used pharmacophore and docking studies to elucidate a new binding pocket for isoprenoid analogues. The unique conformations between the first two isoprene units of 2Z-GGPP, but not GGPP, allows 2Z-GGPP to exploit this new binding pocket. The discovered conformation allows the molecule to adopt a reactive conformation while placing hydrophobic groups within the predominately hydrophobic binding pocket. This computational finding is supported by NMR studies on 13C-labeled 2Z-farnesol, which confirm that the computationally predicted conformation is also favored in solution. These discoveries suggest that ligand conformational flexibility may be an important design consideration for the development of both inhibitors and alternative substrates of FTase.