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Hydrophobicity and functionality maps of farnesyltransferase
S Ahmed1, N Majeux, A Caflisch
1Department of Biochemistry, University of Zürich, Zürich, Switzerland.
Journal of Molecular Graphics & Modelling
|July 14, 2001
Summary
Farnesyltransferase (FTase) is a target for cancer drugs. Computational methods identified key binding sites and designed potential inhibitors, including disubstituted indoles, to block oncogenic Ras protein farnesylation.
Area of Science:
- Biochemistry
- Computational Chemistry
- Drug Discovery
Background:
- Farnesyltransferase (FTase) farnesylates oncogenic Ras proteins, promoting malignant cell transformation.
- FTase is a validated target for anticancer drug development.
Purpose of the Study:
- To investigate the active site of FTase through hydrophobic patch mapping.
- To computationally design novel inhibitors for FTase using the SEED program.
Main Methods:
- Mapping hydrophobic patches within the FTase active site.
- Utilizing the SEED program for exhaustive docking and binding energy evaluation.
- Analyzing electrostatic energy contributions including solvation effects.
Main Results:
- Functionality maps revealed substrate binding site characteristics consistent with sequence variability.
- Identified modifications for potent peptidic inhibitors.
- Designed a library of disubstituted indoles as potential FTase inhibitors.
Conclusions:
- Computational analysis of FTase active site guides inhibitor design.
- Disubstituted indoles show promise for preventing Ras protein binding and oncogenic activity.