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Hydrophobicity and functionality maps of farnesyltransferase

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S. Ahmed; N. Majeux; A. Caflisch

Journal: J. Mol. Graph. Model.
Year: 2001
Volume: 19
Issue: 3-4
Pages: 307-317
DOI: doi:10.1016/S1093-3263(00)00075-9
Type of Publication: Journal Article

Alkyl and Aryl Transferases; Animals; Catalytic Domain; Combinatorial Chemistry Techniques; Computer Simulation; Enzyme Inhibitors; Farnesyltranstransferase; Hydrophobic and Hydrophilic Interactions; Indoles; Ligands; Models, Molecular; Protein Conformation; Software; Substrate Specificity; Thermodynamics


Farnesyltransferase (FTase) catalyzes the attachment of a 15-carbon isoprenoid moiety, farnesyl, through a thioether linkage to a cysteine near the C-terminus of oncogenic Ras proteins. These transform animal cells to a malignant phenotype when farnesylated. Hence, FTase is an interesting target for the development of antitumor agents. In this work we first investigate the active site of FTase by mapping its hydrophobic patches. Then the program SEED is used to dock functional groups into the active site by an exhaustive search and efficient evaluation of the binding energy with solvation. The electrostatic energy is SEED is based on the continuum dielectric approximation and consists of screened intermolecular energy and protein and fragment desolvation terms. The results are found to be consistent with the sequence variability of the tetrapeptide substrate. The distribution of functional groups (functionality maps) on the substrate binding site allows for identification of modifications of the tetrapeptide sequence that are consistent with potent peptidic inhibitors. Furthermore, the best minima of benzene match corresponding moieties of an inhibitor in clinical trials. The functionality maps are also used to design a library of disubstituted indoles that might prevent the binding of the protein substrates.