Target Information
| Target General Information | Top | |||||
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| Target ID |
T86528
(Former ID: TTDI02575)
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| Target Name |
Geranyltranstransferase (FDPS)
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| Synonyms |
KIAA1293; Geranylgeranyl pyrophosphate synthase; Geranylgeranyl diphosphate synthase; GGPS1; GGPPSase; GGPP synthase; Farnesyltranstransferase; Farnesyl pyrophosphate synthase; Farnesyl diphosphate synthase; FPS protein; FPP synthase; Dimethylallyltranstransferase; (2E,6E)-farnesyl diphosphate synthase
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| Gene Name |
FDPS
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Bone paget disease [ICD-11: FB85] | |||||
| 2 | Low bone mass disorder [ICD-11: FB83] | |||||
| 3 | Mineral excesses [ICD-11: 5B91] | |||||
| 4 | Musculoskeletal system/connective tissue disease [ICD-11: FC0Z] | |||||
| Function |
FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate. Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones.
Click to Show/Hide
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| BioChemical Class |
Alkyl aryl transferase
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| UniProt ID | ||||||
| EC Number |
EC 2.5.1.10
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| Sequence |
MPLSRWLRSVGVFLLPAPYWAPRERWLGSLRRPSLVHGYPVLAWHSARCWCQAWTEEPRA
LCSSLRMNGDQNSDVYAQEKQDFVQHFSQIVRVLTEDEMGHPEIGDAIARLKEVLEYNAI GGKYNRGLTVVVAFRELVEPRKQDADSLQRAWTVGWCVELLQAFFLVADDIMDSSLTRRG QICWYQKPGVGLDAINDANLLEACIYRLLKLYCREQPYYLNLIELFLQSSYQTEIGQTLD LLTAPQGNVDLVRFTEKRYKSIVKYKTAFYSFYLPIAAAMYMAGIDGEKEHANAKKILLE MGEFFQIQDDYLDLFGDPSVTGKIGTDIQDNKCSWLVVQCLQRATPEQYQILKENYGQKE AEKVARVKALYEELDLPAVFLQYEEDSYSHIMALIEQYAAPLPPAVFLGLARKIYKRRK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T95CFP | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 8 Approved Drugs | + | ||||
| 1 | Alendronate | Drug Info | Approved | Paget's disease | [2], [3] | |
| 2 | Ibandronate | Drug Info | Approved | Osteoporosis | [4], [5] | |
| 3 | Incadronate | Drug Info | Approved | Hypercalcaemia | [6] | |
| 4 | Minodronate | Drug Info | Approved | Osteoporosis | [6], [7] | |
| 5 | NERIDRONIC ACID | Drug Info | Approved | Bone disease | [6] | |
| 6 | Pamidronate | Drug Info | Approved | Hypercalcaemia | [8], [9] | |
| 7 | Risedronate | Drug Info | Approved | Paget's disease | [10], [11] | |
| 8 | Zoledronate | Drug Info | Approved | Hypercalcaemia | [9] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Zarnestra | Drug Info | Phase 3 | Acute myeloid leukaemia | [12] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | Alendronate | Drug Info | [13] | |||
| 2 | Ibandronate | Drug Info | [13] | |||
| 3 | Zoledronate | Drug Info | [13] | |||
| 4 | OLPADRONIC ACID SODIUM SALT | Drug Info | [31] | |||
| Inhibitor | [+] 62 Inhibitor drugs | + | ||||
| 1 | Incadronate | Drug Info | [14] | |||
| 2 | Minodronate | Drug Info | [14], [15] | |||
| 3 | NERIDRONIC ACID | Drug Info | [16] | |||
| 4 | Pamidronate | Drug Info | [17] | |||
| 5 | Risedronate | Drug Info | [18], [19] | |||
| 6 | Zarnestra | Drug Info | [20] | |||
| 7 | (1-hydroxy-1-phosphono-heptyl)-phosphonic acid | Drug Info | [21] | |||
| 8 | (2E, 6E)-farnesylbisphosphonate | Drug Info | [22] | |||
| 9 | (biphenyl-3-ylamino)methylenediphosphonic acid | Drug Info | [23] | |||
| 10 | 1-(but-2-ylamino)ethyl 1,I-bisphosphonic acid | Drug Info | [21] | |||
| 11 | 1-[(cyclohexylamino)ethyl]-1,1-bisphosphonicacid | Drug Info | [21] | |||
| 12 | 1-[(n-but-1-ylamino)ethyl]-1,1-bisphosphonic acid | Drug Info | [21] | |||
| 13 | 1-[(n-hex-1-ylamino)ethyl]-1,1-bisphosphonic acid | Drug Info | [21] | |||
| 14 | 1-[(n-oct-1-ylamino)ethyl]-1,1-bisphosphonic acid | Drug Info | [21] | |||
| 15 | 1-[(prop-1-ylamino)ethyl]-1,1-bisphosphonic acid | Drug Info | [21] | |||
| 16 | 1-[(prop-2-ylamino)ethyl]-1,1-bisphosphonicacid | Drug Info | [21] | |||
| 17 | 1-[(tert-butylamino)ethyl]-1,1-bisphosphonicacid | Drug Info | [21] | |||
| 18 | 3-azageranylgeranyl diphosphate | Drug Info | [24] | |||
| 19 | BPH-252 | Drug Info | [1] | |||
| 20 | BPH-608 | Drug Info | [25] | |||
| 21 | BPH-628 | Drug Info | [1] | |||
| 22 | BPH-629 | Drug Info | [25] | |||
| 23 | BPH-675 | Drug Info | [25] | |||
| 24 | BPH-676 | Drug Info | [25] | |||
| 25 | BPH-715 | Drug Info | [1] | |||
| 26 | BPH-742 | Drug Info | [1] | |||
| 27 | CT-10 | Drug Info | [26] | |||
| 28 | digeranyl bisphosphonate | Drug Info | [1] | |||
| 29 | Dimethylallyl Diphosphate | Drug Info | [27] | |||
| 30 | diphosphoric acid | Drug Info | [16] | |||
| 31 | Geranyl Diphosphate | Drug Info | [28] | |||
| 32 | GERANYLGERANYL DIPHOSPHATE | Drug Info | [27] | |||
| 33 | Homorisedronate | Drug Info | [29] | |||
| 34 | ISOPENTENYL PYROPHOSPHATE | Drug Info | [27] | |||
| 35 | Isopentyl Pyrophosphate | Drug Info | [28] | |||
| 36 | NE-10575 | Drug Info | [16] | |||
| 37 | NE10790 | Drug Info | [16] | |||
| 38 | NE11808 | Drug Info | [16] | |||
| 39 | NE21650 | Drug Info | [30] | |||
| 40 | NE58018 | Drug Info | [16] | |||
| 41 | NE58027 | Drug Info | [16] | |||
| 42 | NE58043 | Drug Info | [16] | |||
| 43 | NE58062 | Drug Info | [16] | |||
| 44 | NE97220 | Drug Info | [16] | |||
| 45 | PG-1014491 | Drug Info | [26] | |||
| 46 | Piridronic acid | Drug Info | [16] | |||
| 47 | PMID12014956C12 | Drug Info | [24] | |||
| 48 | PMID17963374C31 | Drug Info | [32] | |||
| 49 | PMID17975902C5e | Drug Info | [33] | |||
| 50 | PMID18295483C2 | Drug Info | [34] | |||
| 51 | PMID18800762C11 | Drug Info | [1] | |||
| 52 | PMID18800762C14 | Drug Info | [1] | |||
| 53 | PMID18800762C16 | Drug Info | [1] | |||
| 54 | PMID18800762C19 | Drug Info | [1] | |||
| 55 | PMID18800762C47 | Drug Info | [1] | |||
| 56 | PMID18800762C51 | Drug Info | [1] | |||
| 57 | [2-(6-Chloro-purin-9-yl)ethyl]-bisphosphonic acid | Drug Info | [35] | |||
| 58 | [2-(Benzoimidazol-1-yl)ethyl]-bisphosphonic acid | Drug Info | [35] | |||
| 59 | [2-(Imidazol-1-yl)ethyl]-bisphosphonic acid | Drug Info | [35] | |||
| 60 | [2-(Imidazol-2-yl-thio)ethyl]-bisphosphonic acid | Drug Info | [35] | |||
| 61 | [2-(Purin-9-yl)ethyl]-bisphosphonic acid | Drug Info | [35] | |||
| 62 | [2-(Pyrazol-1-yl)ethyl]-bisphosphonic acid | Drug Info | [35] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 4 BioCyc Pathways | + | ||||
| 1 | Superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate) | |||||
| 2 | Superpathway of cholesterol biosynthesis | |||||
| 3 | Trans, trans-farnesyl diphosphate biosynthesis | |||||
| 4 | Geranylgeranyldiphosphate biosynthesis | |||||
| KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
| 1 | Terpenoid backbone biosynthesis | |||||
| 2 | Metabolic pathways | |||||
| 3 | Biosynthesis of antibiotics | |||||
| 4 | Influenza A | |||||
| 5 | HTLV-I infection | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Cholesterol biosynthesis | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Steroid Biosynthesis | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Cholesterol biosynthesis | |||||
| 2 | Activation of gene expression by SREBF (SREBP) | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | Activation of Gene Expression by SREBP (SREBF) | |||||
| 2 | SREBP signalling | |||||
| 3 | Cholesterol Biosynthesis | |||||
| References | Top | |||||
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| REF 1 | Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J Med Chem. 2008 Sep 25;51(18):5594-607. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3141). | |||||
| REF 3 | Osteonecrosis of the jaw. South Med J. 2008 Feb;101(2):160-5. | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3059). | |||||
| REF 5 | Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med. 2009 Feb;122(2 Suppl):S14-21. | |||||
| REF 6 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007280) | |||||
| REF 8 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7259). | |||||
| REF 9 | Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008 Dec;13(4):609-27. | |||||
| REF 10 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3176). | |||||
| REF 11 | Risedronate for treatment of osteoporosis. Nippon Rinsho. 2009 May;67(5):948-53. | |||||
| REF 12 | ClinicalTrials.gov (NCT00093990) Tipifarnib Versus Best Supportive Care in the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML). U.S. National Institutes of Health. | |||||
| REF 13 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. | |||||
| REF 14 | Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001 Feb;296(2):235-42. | |||||
| REF 15 | Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid. J Med Chem. 2010 May 13;53(9):3454-64. | |||||
| REF 16 | Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of hu... J Med Chem. 2008 Apr 10;51(7):2187-95. | |||||
| REF 17 | Detection of nonsterol isoprenoids by HPLC-MS/MS. Anal Biochem. 2008 Dec 1;383(1):18-24. | |||||
| REF 18 | Activity of bisphosphonates against Trypanosoma brucei rhodesiense. J Med Chem. 2002 Jul 4;45(14):2904-14. | |||||
| REF 19 | In vivo activities of farnesyl pyrophosphate synthase inhibitors against Leishmania donovani and Toxoplasma gondii. Antimicrob Agents Chemother. 2002 Mar;46(3):929-31. | |||||
| REF 20 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 21 | Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl... Bioorg Med Chem. 2008 Mar 15;16(6):3283-90. | |||||
| REF 22 | Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. Bioorg Med Chem. 2008 Jan 1;16(1):390-9. | |||||
| REF 23 | Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR i... Bioorg Med Chem. 2008 Oct 1;16(19):8959-67. | |||||
| REF 24 | Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents. J Med Chem. 2002 May 23;45(11):2185-96. | |||||
| REF 25 | Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. | |||||
| REF 26 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 643). | |||||
| REF 27 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 28 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 29 | Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase. J Biol Chem. 2001 Sep 7;276(36):33930-7. | |||||
| REF 30 | Identification of a bisphosphonate that inhibits isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Biochem Biophys Res Commun. 2002 Jan 18;290(2):869-73. | |||||
| REF 31 | Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem Biophys Res Commun. 1999 Feb 16;255(2):491-4. | |||||
| REF 32 | Activity of sulfonium bisphosphonates on tumor cell lines. J Med Chem. 2007 Nov 29;50(24):6067-79. | |||||
| REF 33 | Synthesis and biological evaluation of alpha-halogenated bisphosphonate and phosphonocarboxylate analogues of risedronate. J Med Chem. 2007 Nov 29;50(24):5967-75. | |||||
| REF 34 | Design and structure-activity relationships of potent and selective inhibitors of undecaprenyl pyrophosphate synthase (UPPS): tetramic, tetronic acids and dihydropyridin-2-ones. Bioorg Med Chem Lett.2008 Mar 15;18(6):1840-4. | |||||
| REF 35 | Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocy... J Med Chem. 2008 Nov 13;51(21):6800-7. | |||||
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