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New insights into human farnesyl pyrophosphate synthase inhibition by second-generation bisphosphonate drugs

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Abstract

Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibition of the human Farnesyl Pyrophosphate Synthase (hFPPS). Available inhibitory activity values show that 2G-BPs act time-dependently, showing big differences in their initial inhibitory activities but similar final IC50 values. However, there is a lack of information explaining this similar final inhibitory potency. Although different residues have been identified in the stabilization of the R2 side chain of 2G-BPs into the active site, similar free binding energies were obtained that highlighted a similar stability of the ternary complexes, which in turns justified the similar IC50 values reported. Free binding energy calculations also demonstrated that the union of 2G-BPs to the active site were 38 to 54 kcal mol−1 energetically more favourable than the union of the natural substrate, which is the basis of the inhibition potency of the hFPPS activity.

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References

  1. Giger EV, Castagner B, Leroux JC (2013) J Control Release 167:175–188

    Article  CAS  Google Scholar 

  2. Li B, Chau JFL, Wang X, Leong WF (2011) J Cell Biochem 112:1229–1242

    Article  CAS  Google Scholar 

  3. Russell RGG, Rogers MJ, Frith JC, Luckman SP, Coxon FP, Benford HL, Croucher PI, Shipman C, Fleish HA (1999) J Bone Miner Res 14:53–65

    Article  CAS  Google Scholar 

  4. Frith JC, Mönkkönen J, Auriola S, Mönkkönen H, Rogers MJ (2001) Arthritits Rheum 44:2201–2210

    Article  CAS  Google Scholar 

  5. Frith JC, Mönkkönen J, Blackburn M, Russell RGG, Rogers MJ (1997) J Bone Miner Res 12:1358–1367

    Article  CAS  Google Scholar 

  6. Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC (2000) Cancer 88:2961–2978

    Article  CAS  Google Scholar 

  7. Schenk R, Eggli P., Fleisch H, Rosini S (1986) Calcif Tissue Int 38:349–349

    Article  Google Scholar 

  8. Muhlbauer RC, Bauss F, Schenk R, Janner M, Bosies E, Strein K, Fleisch H (1991) J Bone Miner Res 6:1003–1011

    Article  CAS  Google Scholar 

  9. U.S. Food and Drug Administration (2015) FDA approved drug products. Retrived from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

  10. European Medicines Agency, EMA (2015) European public assessment reports. Retrived from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124

  11. Gatti D, Rossini M, Viapiana O, Idolazzi L, Adami S (2013) Ther Clin Risk Manag 9:139–147

    Article  CAS  Google Scholar 

  12. O’Rourke NP, McCloskey EV, Rosini S, Coleman RE, Kanis JA (1994) Br J Cancer 69:914–917

    Article  Google Scholar 

  13. Jang SW, Lee JW, Ryu DS, Son M, Kang MJ (2014) Int J Biol Macromol 70:174–178

    Article  CAS  Google Scholar 

  14. Jeal W, Barradell LB, Mctavish D (1997) Drugs 53(3):415–434

    Article  CAS  Google Scholar 

  15. Ott SM (2012) Kidney Int 82:833–835

    Article  CAS  Google Scholar 

  16. CADIME (2010) Boletín Terapéutico Andaluz 26(2):1–4

    Google Scholar 

  17. Loke YK, Jeevanantham V, Singh S (2009) Drug Saf 32(3):219–228

    Article  CAS  Google Scholar 

  18. Majumdar SR (2008) BMJ 336(7648):784–785

    Article  Google Scholar 

  19. Fraunfelder FW, Fraunfelder FT (2004) Ophthalmology 111(7):1275–1279

    Article  CAS  Google Scholar 

  20. Hess LM, Jeter JM, Benham-Hutchins M, Alberts DS (2008) Am J Med 121:475–483

    Article  CAS  Google Scholar 

  21. Bauss F, Pfister T, Papapoulos S (2008) J Bone Miner Metab 26:406–408

    Article  CAS  Google Scholar 

  22. Ruggiero SL, Mehrotra B (2009) Annu Rev Med 60:85–96

    Article  CAS  Google Scholar 

  23. Whitaker M, Guo J, Kehoe T, Benson G (2012) N Engl J Med 366:2048–2051

    Article  CAS  Google Scholar 

  24. Park-Wyllie LP, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler JP, Laupacis A (2011) J Am Med Assoc 305:783–789

    Article  CAS  Google Scholar 

  25. Papapoulos SE, E.M.W. Eekhoff, Zwinderman AH (2006) J Bone Miner Res 21:88–91

    Article  Google Scholar 

  26. Koyama T, Saito A, Ogura K, Seto S (1980) J Am Chem Soc 102:3614–3618

    Article  CAS  Google Scholar 

  27. Luckman SP, Coxon FP, Ebetino FH, Russell RG, Rogers MJ (1998) J Bone Miner Res 13:1668–1678

    Article  CAS  Google Scholar 

  28. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA (1999) Proc Natl Acad Sci USA 96:133–138

    Article  CAS  Google Scholar 

  29. Sinensky M (2000) Biochim Biophys Acta 1484:93–106

    Article  CAS  Google Scholar 

  30. Zhang FL, Casey PJ (1996) Annu Rev Biochem 65:241–269

    Article  CAS  Google Scholar 

  31. Zhang Y, Cao R, Yin F, Hudock MP, Guo R-T, Krysiak K, Mukherjee S, Gao Y-G, Robinson J, Song Y, No JH, Bergan K, Leon A, Cass L, Goddard A, Chang T-K, Lin F-Y, Van Beek E, Papapoulos S, Wang AH-J, Kubo T, Ochi M, Mukkamala D, Oldfield E (2009) J Am Chem Soc, 131:5153–5162

    Article  CAS  Google Scholar 

  32. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Opperman U (2006) Proc Natl Acad Sci USA 103:7829–7834

    Article  CAS  Google Scholar 

  33. Rondeau JM, Bitsch F, Bourgier E, Geiser M, Hemmig R, Kroemer M, Lehmann S, Ramage P, Rieffel S, Strauss A, Green JR, Jahnke W (2006) Chem Med Chem 1:267–273

    Article  CAS  Google Scholar 

  34. Park J, Lin Y-S, Tsantrizos Y-S, Berghuis AM (2014) Acta Cryst 70:299–304

    CAS  Google Scholar 

  35. Fernández D, Ortega-Castro J, Mariño L, Perelló J, Frau J (2015) J Comput Aided Mol Des 29:667–680

    Article  Google Scholar 

  36. Ohno K, Mori K, Orita M, Takeuchi M (2011) Curr Med Chem 18:220–233

    Article  CAS  Google Scholar 

  37. Fraser J, Glickman FJ, Schmid A (2007) Assay Drug Dev Technol 5:205–214

    Article  Google Scholar 

  38. Poulter CD, Rilling HC (1978) Acc Chem Res 11:307–313

    Article  CAS  Google Scholar 

  39. Holloway PW, Popjak G (1967) Biochem J, 104:57–70

    Article  CAS  Google Scholar 

  40. Martin MB, Arnold W, Heath HT, Urbina JA, Oldfield E (1999) Biochem Biophys Res Commun 263:754–758

    Article  CAS  Google Scholar 

  41. Park J, Lin Y-S, De Schutter JW, Tsantrizos YS, Berghuis AM (2012) BMC Struct Biol 12:32

    Article  CAS  Google Scholar 

  42. Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH, Russell RGG, Oppermann U, Kavanagh KL (2008) J Med Chem, 51:2187–2195

    Article  CAS  Google Scholar 

  43. Fernández D, Ortega-Castro J, Frau J (2013) J Comput Aided Mol Des 27:739–754

    Article  Google Scholar 

  44. Gabelli SB, McLellan JS, Montalvetti A, Oldfield E, Docampo R, Amzel LM (2006) Proteins 62:80–88

    Article  CAS  Google Scholar 

  45. Tsoumpra MK, Muniz JR, Barnett BL, Kwaasi AA, Pilka ES, Kavanagh KL, Evdokimov A, Walter RL, Delft FV, Ebetino FH, Oppermann U, R.G.G. Russell, Dunford JE (2015) Bone 81:478–486

    Article  CAS  Google Scholar 

  46. N.N.F.S.A. Cerqueira, Ribeiro J, Fernandes PA, Ramos MJ (2011) Int J Quantum Chem, 111:1208–1212

    Article  CAS  Google Scholar 

  47. Humphrey W, Dalke A, Schulten K (1996) J Molec Graphics 14:33–38

    Article  CAS  Google Scholar 

  48. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  49. Reed AE, Weinstock RB, Weinhold F (1985) J Chem Phys 83:735–746

    Article  CAS  Google Scholar 

  50. Reed AE, Curtiss LA, Weinhold F (1988) Chem Rev, 88:899–926

    Article  CAS  Google Scholar 

  51. Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Götz AW, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh MJ, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2012) AMBER 12. University of California, San Francisco

    Google Scholar 

  52. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T (2003) J Comput Chem 24:1999–2012

    Article  CAS  Google Scholar 

  53. Lee MC, Duan Y (2004) Proteins 55:620–634

    Article  CAS  Google Scholar 

  54. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem, 25:1157–1174

    Article  CAS  Google Scholar 

  55. Meagher KL, Redman LT, Carlson HA (2003) J Comp Chem, 24:1016–1025

    Article  CAS  Google Scholar 

  56. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03, Revision C.02 Gaussian Inc., Wallingford CT

  57. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  58. Bekker H, Berendsen HJC, Dijkstra EJ, Achterop S, van Drunen R, van der Spoel D, Sijbers A, Keegstra H, Reitsma B, M.K.R. Renardus (1993) In: de Groot RA, Nadrchal J Physics computing 92, World Scientific Publishing, Singapore

  59. Berendsen HJC, van der Spoel D, van Drunen R (1995) Comp Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  60. Lindahl E, Hess B, van der Spoel D (2001) J Mol Model 7:306–317

    Article  CAS  Google Scholar 

  61. van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) J Comp Chem 26:1701–1718

    Article  Google Scholar 

  62. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) J Chem Theory Comp 4:435–447

    Article  CAS  Google Scholar 

  63. Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  64. B. Hess B (2008) J Chem Theory Comput 4:116–122

    Article  Google Scholar 

  65. Berendsen HJC, Postma JPM, Vangunsteren WF, Dinola A, Haak JR (1984) J Chem Phys, 81:3684–3690

    Article  CAS  Google Scholar 

  66. Parrinello M, Rahman A (1981) J Appl Phys, 52:7182–7190

    Article  CAS  Google Scholar 

  67. Pohorille A, Jarzynski C, Chipot C (2010) J Phys Chem B 114:10235–10253

    Article  CAS  Google Scholar 

  68. Bennett CH (1976) J Comput Phys 22:245–268

    Article  Google Scholar 

  69. Dixit SB, Chipot C (2001) J Phys Chem A 105:9795–9799

    Article  CAS  Google Scholar 

  70. Haynes WM CRC Handbook of Chemistry and Physics, 93rd edn. Taylor & Francis Group, Abingdon

  71. Johnson ER, Keinan S, Mori-Sanchez P, Contreras-Garcia J, Cohen AJ, Yang W (2010) J Am Chem Soc 132:6498–6506

    Article  CAS  Google Scholar 

  72. Contreras-García J, Johnson ER, Keinan S, Chaudret R, Piquemal J-P, Beratan DN, Yang W (2011) J Chem Theory Comput 7:625–632

    Article  Google Scholar 

  73. Virnau P, Müller M (2004) J Chem Phys 120:10925–10930

    Article  CAS  Google Scholar 

  74. Torrie GM, Valleau JP (1977) J Comput Phys 23:187–199

    Article  Google Scholar 

Download references

Acknowledgements

This work was funded by the Conselleria d’Educació, Cultura i Universitats (Ajuts a accions especials d’R+D AAEE044/2012 and AAEE027/2014). The authors are grateful to Sanifit Laboratoris S.L. for financial support for this research. One of us (D.F.) wishes to acknowledge the Spanish MEC for his Ph.D. grant (AP2010-6043) within the FPU program.

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Authors and Affiliations

  1. Department de Química, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, 07122, Palma, Spain

    D. Fernández, R. Ramis, J. Ortega-Castro, B. Vilanova & J. Frau

  2. Instituto de Investigación Sanitaria de Palma (IdISPa), 07010, Palma, Spain

    D. Fernández, R. Ramis, J. Ortega-Castro, B. Vilanova & J. Frau

  3. Institute of Neuroscience and Medicine INM-9, Institute for Advanced Simulations IAS-5, Computational Biomedicine, Forschungszentrum Jülich, Jülich, Germany

    R. Casasnovas

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  1. D. Fernández
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Fernández, D., Ramis, R., Ortega-Castro, J. et al. New insights into human farnesyl pyrophosphate synthase inhibition by second-generation bisphosphonate drugs. J Comput Aided Mol Des 31, 675–688 (2017). https://doi.org/10.1007/s10822-017-0034-5

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