Abstract
Farnesyltransferase (FT) inhibitors can repress tumor cell proliferation without substantially interfering with normal cell growth and are thus promising in cancer treatment. A detailed knowledge of how substrates and inhibitors bind to FT at the atomic level can expedite screening and rational design of improved FT inhibitors. Here we report theoretical models of the FT complexed with FPP and the potent nonpeptidic inhibitor SCH 56580 and other inhibitor-FPP-FT ternary complexes derived from the docking studies prior to any crystal structures of the FT liganded with nonpeptidic inhibitors. On the basis of these models we evaluate the roles of FPP, Zn2+ and the zinc-coordinated water molecule in inhibitor binding, and propose the structural determinants of binding of nonpeptidic FT inhibitors. Furthermore, we suggest the use of the FPP-FT binary complex as a novel and effective drug target structure for screening and rational design of improved FT inhibitors.
Original language | English (US) |
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Pages (from-to) | 203-217 |
Number of pages | 15 |
Journal | Journal of Molecular Modeling |
Volume | 5 |
Issue number | 10 |
DOIs | |
State | Published - 1999 |
Keywords
- Antiangiogenesis
- Antiproliferation
- Docking study
- Drug design
- Ras mutation
ASJC Scopus subject areas
- Catalysis
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry
- Computational Theory and Mathematics