title: Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: a 3D-QSAR study.
abstract: We report the results of a comparative molecular field analysis and comparative molecular similarity index analysis of the human farnesyl pyrophosphate synthase (FPPS) inhibition by nitrogen bisphosphonates (NBPs) taking into account their time-dependent inhibition efficacies. The 3D-QSAR models obtained provide steric, electrostatic and hydrophobic contour maps consistent with the interactions into the active site of human FPPS observed in available crystallographic structures. Furthermore, the 3D-QSAR models obtained provide accurately IC50 values of the NBPs of the training set. The predictive ability of these 3D-QSAR models was found to rely on the choice of biologically active conformations of the target molecules and on a careful examination of the protonation status of the NBPs in the training set. The best models obtained can be useful to predict biological values of a high number of NBPs that have been used for the treatment of different diseases as potential inhibitors of the activity of the FPPS enzyme.
authors: Departament de Química, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, 07122, Spain.
authors: David
authors: D
authors: Fernández
authors: Joaquín
authors: J
authors: Ortega-Castro
authors: Juan
authors: J
authors: Frau
mesh_terms: D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase; D009584:Nitrogen
references: J Med Chem. 2003 Jul 3;46(14):2932-44
references: 12825934
references: J Med Chem. 1994 Nov 25;37(24):4130-46
references: 7990113
references: Annu Rev Pharmacol Toxicol. 1998;38:375-88
references: 9597160
references: Curr Med Chem. 2011;18(2):220-33
references: 21110804
references: JAMA. 2011 Feb 23;305(8):783-9
references: 21343577
references: SAR QSAR Environ Res. 2000;11(3-4):189-209
references: 10969871
references: J Am Chem Soc. 1988 Aug 1;110(18):5959-67
references: 22148765
references: J Med Chem. 2002 Jul 4;45(14):2894-903
references: 12086477
references: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7829-34
references: 16684881
references: J Med Chem. 2008 Apr 10;51(7):2187-95
references: 18327899
references: Biochemistry. 1994 Sep 13;33(36):10871-7
references: 8086404
references: J Cell Biochem. 2011 May;112(5):1229-42
references: 21465521
references: Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15018-23
references: 8986756
references: N Engl J Med. 2012 May 31;366(22):2048-51
references: 22571168
references: J Biol Chem. 2007 Apr 27;282(17):12377-87
references: 17329254
references: Am J Med. 2008 Jun;121(6):475-483.e3
references: 18501224
references: J Med Chem. 2002 Jul 4;45(14):2904-14
references: 12086478
references: Annu Rev Biochem. 1996;65:241-69
references: 8811180
references: Br J Haematol. 1997 Sep;98(3):665-72
references: 9332325
references: Cancer Lett. 2007 Nov 8;257(1):16-35
references: 17697748
references: ChemMedChem. 2006 Feb;1(2):267-73
references: 16892359
references: Ann Oncol. 2005 May;16(5):687-95
references: 15802276
references: Acta Crystallogr Sect E Struct Rep Online. 2011 Apr 1;67(Pt 4):o1025
references: 21754041
references: Biochem Biophys Res Commun. 1999 Oct 5;263(3):754-8
references: 10512752
references: Biochim Biophys Acta. 2000 Apr 12;1484(2-3):93-106
references: 10760460
references: J Am Chem Soc. 2009 Apr 15;131(14):5153-62
references: 19309137
references: J Bone Miner Metab. 2008;26(4):406-8
references: 18600409
references: Proteins. 2006 Jan 1;62(1):80-8
references: 16288456
references: J Med Chem. 2012 Apr 12;55(7):3201-15
references: 22390415
references: Ann N Y Acad Sci. 2007 Nov;1117:209-57
references: 18056045
references: J Med Chem. 2003 Nov 20;46(24):5171-83
references: 14613320
references: J Clin Endocrinol Metab. 1993 Jun;76(6):1397-8
references: 8501141
references: Blood. 2003 Jul 1;102(1):200-6
references: 12623838
references: J Bone Miner Res. 1997 Sep;12(9):1358-67
references: 9286751
references: Annu Rev Med. 2009;60:85-96
references: 18928335
references: J Mol Graph Model. 2002 Jan;20(4):269-76
references: 11858635
references: Mol Med. 2001 Oct;7(10):711-22
references: 11713370