title: Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation.
abstract: 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.
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Cammy
authors.initials: C
authors.lastname: K-M Chen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hudock
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rey-Ting
authors.initials: RT
authors.lastname: Guo
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: Joo Hwan
authors.initials: JH
authors.lastname: No
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Liang
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.forename: Tao-Hsin
authors.initials: TH
authors.lastname: Chang
authors.forename: Shiou-Chi
authors.initials: SC
authors.lastname: Chang
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Jordan
authors.initials: J
authors.lastname: Axelson
authors.forename: Anup
authors.initials: A
authors.lastname: Kumar
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase
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