Modeling of inhibition mechanism of natural ligands to farnesyl protein transferase using molecular docking

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Title
Modeling of inhibition mechanism of natural ligands to farnesyl protein transferase using molecular docking
Author(s)
N D Sung; Y G Cheun; Byoung-Mog Kwon; H Y Park; C K Kim
Bibliographic Citation
Bulletin of Korean Chemical Society, vol. 24, no. 10, pp. 1509-1511
Publication Year
2003
Abstract
Ras Proteins play important roles in the signal trans-duction necessary for the cell growth. In the tumour cells, approximately 30% of the Ras protein genes are mutated. 1 Ras proteins (H, N, and K) are small guanine nucleotide binding proteins that undergo a series of post-translational modifications including the farnesylation on the thiol group at the Ras C-terminus catalyzed by the farnesyl protein transferase (FPTase). 2 This is a mandatory process before anchoring to plasma membrane which is critical for its biological activity, e.g. cell proliferation and tumorigenesis. Recent work has demonstrated that specific inhibition of the FPTase might be interesting to find effective therapeutical agents for the treatment of cancer. 3 Many synthetic FPTase inhibitors have been tested including peptidomimetics in the past few years. However, a few examples of natural products inhibitors were reported. In a recent work, many natural ligands were isolated as possible inhibitors of FPTase. 4 In the course of their screen-ing for protein inhibitors from herbal medicines, several compounds including arteminolide A (1) and artenomaloide B (2) were reported. 1 was identified as a configurational isomer of 2. 1 strongly inhibited FPTase (IC 50 = 0.36 M) but 2 inhibits weakly (IC 50 = 200 M). Molecular Modeling In this work, molecular docking studies between a bio-macromolecule and 1 or 2 were performed in order to identify their biological activity differences using the modules implemented in the molecular modeling package SYBYL. 5 The FPTase protein (code name: 1QBQ) used for the docking is available from the Protein Data Bank. 6 FPTase is a zinc heterodimeric metalloenzyme complexed with farnesyl pyrophosphate (FPP) and Ca1a2X consensus motif, where a1 and a2 are aliphatic amino acids and X can be any residue, at 2.5 A resolution. In an extensive docking study 7 using Biodock program, four different binding modes were postulated depending on the physicochemical properties of natural ligands: (1) Non specific (2) Zn 2+ shielding (3) Peptidomimetic (4) FPPmimetic. If a natural compound has molecular volume similar to that of Ca 1 a 2 X motif, it can inhibit the FPTase occupying selectively the binding site of peptide substrate, and thus can be defined as a peptidomimetic inhibitor.
Keyword
Farnesyl protein transferase inhibitorMolecular dockingMolecular modeling
ISSN
0253-2964
Publisher
Wiley
DOI
http://dx.doi.org/10.5012/bkcs.2003.24.10.1509
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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