Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation.
We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg (2+) that occupy the same position as found in FPP synthase. However, each of three "V-shaped" bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 A. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2x by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents.
K-M Chen
Cammy
C
Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
Hudock
Michael P
MP
Zhang
Yonghui
Y
Guo
Rey-Ting
RT
Cao
Rong
R
No
Joo Hwan
JH
Liang
Po-Huang
PH
Ko
Tzu-Ping
TP
Chang
Tao-Hsin
TH
Chang
Shiou-Chi
SC
Song
Yongcheng
Y
Axelson
Jordan
J
Kumar
Anup
A
Wang
Andrew H-J
AH
Oldfield
Eric
E
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020014:K562 Cells; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase
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