Journal of Computer-Aided Molecular Design

, Volume 19, Issue 12, pp 871–885 | Cite as

Protein farnesyltransferase: Flexible docking studies on inhibitors using computational modeling

  • Wayne C. Guida
  • Andrew D. Hamilton
  • Justin W. Crotty
  • Saïd M. Sebti


Using MacroModel, peptide, peptidomimetic and non-peptidomimetic inhibitors of the zinc metalloenzyme, farnesyltransferase (FTase), were docked into the enzyme binding site. Inhibitor flexibility, farnesyl pyrophosphate substrate flexibility, and partial protein flexibility were taken into account in these docking studies. In addition to CVFM and CVIM, as well as our own inhibitors FTI-276 and FTI-2148, we have docked other farnesyltransferase inhibitors (FTIs) including Zarnestra, which presently is in advanced clinical trials. The AMBER* force field was employed, augmented with parameters that were derived for zinc. A single binding site model that was derived from the crystal structure of CVFM complexed with farnesyltransferase and farnesylpyrophosphate was used for these studies. The docking results using the lowest energy structure from the simulation, or one of the lowest energy structures, were generally in excellent agreement with the X-ray structures. One of the most important findings of this study is that numerous alternative conformations for the methionine side chain can be accommodated by the enzyme suggesting that the methionine pocket can tolerate groups larger than methionine at the C-terminus of the tetrapeptide and suggesting alternative locations for the placement of side chains that may improve potency.


docking, drug design, flexible docking, molecular modeling, protein farnesyltransferase 


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We thank the National Institutes of Health (CA67771) for financial support of this work. We also thank Dr. Corey Strickland of Schering Plough for supplying us with the coordinates of the X-ray structures of FTI-276 and FTI-2148. We thank Mr. Matt Maderios of Eckerd College for assistance with the docking studies performed on DPI-1.


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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Wayne C. Guida
    • 1
    • 2
  • Andrew D. Hamilton
    • 3
  • Justin W. Crotty
    • 2
  • Saïd M. Sebti
    • 1
  1. 1.Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Departments of Oncology and Biochemistry & Molecular Biology, College of MedicineUniversity of South FloridaTampaUSA
  2. 2.Department of ChemistryEckerd CollegeSt. PetersburgUSA
  3. 3.Department of ChemistryYale UniversityNew HavenUSA

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