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.

[1]  M. Cassera,et al.  A Solanesyl-diphosphate Synthase Localizes in Glycosomes of Trypanosoma cruzi* , 2006, Journal of Biological Chemistry.

[2]  G. Klebe,et al.  Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. , 1994, Journal of medicinal chemistry.

[3]  E. Oldfield,et al.  Activity of sulfonium bisphosphonates on tumor cell lines. , 2007, Journal of medicinal chemistry.

[4]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[5]  D E McRee,et al.  XtalView/Xfit--A versatile program for manipulating atomic coordinates and electron density. , 1999, Journal of structural biology.

[6]  P. Clézardin,et al.  Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. , 2005, Cancer research.

[7]  Eric Oldfield,et al.  Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: Implications for drug design , 2005, Proteins.

[8]  H. Hirabayashi,et al.  Relationship Between Physicochemical and Osteotropic Properties of Bisphosphonic Derivatives: Rational Design for Osteotropic Drug Delivery System (ODDS) , 2001, Pharmaceutical Research.

[9]  E. Oldfield,et al.  Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases , 2007, Proceedings of the National Academy of Sciences.

[10]  Wolfgang Jahnke,et al.  Structural Basis for the Exceptional in vivo Efficacy of Bisphosphonate Drugs , 2006, ChemMedChem.

[11]  R. Hohl,et al.  Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. , 2007, Biochemical and biophysical research communications.

[12]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[13]  E. Oldfield,et al.  Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis. , 1999, Biochemical and biophysical research communications.

[14]  A. H. Wang,et al.  Crystal Structure of Type-III Geranylgeranyl Pyrophosphate Synthase from Saccharomyces cerevisiae and the Mechanism of Product Chain Length Determination* , 2006, Journal of Biological Chemistry.

[15]  Udo Oppermann,et al.  The Crystal Structure of Human Geranylgeranyl Pyrophosphate Synthase Reveals a Novel Hexameric Arrangement and Inhibitory Product Binding* , 2006, Journal of Biological Chemistry.

[16]  T. Halgren.  Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[17]  Bruce L. Bush,et al.  Sample-distance partial least squares: PLS optimized for many variables, with application to CoMFA , 1993, J. Comput. Aided Mol. Des..

[18]  E. Oldfield,et al.  3-D QSAR investigations of the inhibition of Leishmania major farnesyl pyrophosphate synthase by bisphosphonates. , 2003, Journal of medicinal chemistry.

[19]  G. Crippen,et al.  Prediction of Physicochemical Parameters by Atomic Contributions. , 1999 .

[20]  R. Hohl,et al.  Synthesis and biological activity of isoprenoid bisphosphonates. , 2006, Bioorganic & medicinal chemistry.

[21]  I. Sagami,et al.  Human Geranylgeranyl Diphosphate Synthase , 1999, The Journal of Biological Chemistry.

[22]  J. Buolamwini,et al.  Receptor-guided alignment-based comparative 3D-QSAR studies of benzylidene malonitrile tyrphostins as EGFR and HER-2 kinase inhibitors. , 2003, Journal of medicinal chemistry.

[23]  E. Oldfield,et al.  Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption. , 2005, Journal of medicinal chemistry.

[24]  M. Thoulouzan,et al.  Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells , 2006, BMC Cancer.

[25]  D. Hosfield,et al.  Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis , 2004 .

[26]  J. Aqvist,et al.  A new method for predicting binding affinity in computer-aided drug design. , 1994, Protein engineering.

[27]  E. Oldfield,et al.  Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents. , 2002, Journal of medicinal chemistry.

[28]  Ho-Jin Park,et al.  3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Interfere With Angiogenesis by Inhibiting the Geranylgeranylation of RhoA , 2002, Circulation research.

[29]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[30]  B. Camara,et al.  Carotenoid biosynthesis: Isolation and characterization of a bifunctional enzyme catalyzing the synthesis of phytoene. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[31]  A. Brünger.  Assessment of phase accuracy by cross validation: the free R value. Methods and applications. , 1993, Acta crystallographica. Section D, Biological crystallography.

[32]  E. Keystone,et al.  Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts , 2006, Arthritis research & therapy.

[33]  S. Knapp,et al.  The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  J. Sacchettini,et al.  Crystal structure of recombinant farnesyl diphosphate synthase at 2.6-A resolution. , 1994, Biochemistry.