Abstract：
: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 (13)C-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.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Henriksen BS,Zahn TJ,Evanseck JD,Firestine SM,Gibbs RAdoi
10.1021/ci0496550keywords:
subject
Has Abstractpub_date
2005-07-01 00:00:00pages
1047-52issue
4eissn
1549-9596issn
1549-960Xjournal_volume
45pub_type
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