Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase

Journal of the American Chemical Society
Fenglin YinEric Oldfield

Abstract

We report the results of an ITC (isothermal titration calorimetry) investigation of the binding of six bisphosphonates to the enzyme farnesyl diphosphate synthase (FPPS; EC 2.5.1.10) from Trypanosoma brucei. The bisphosphonates investigated were zoledronate, risedronate, ibandronate, pamidronate, 2-phenyl-1-hydroxyethane-1,1-bisphosphonate, and 1-(2,2-bisphosphonoethyl)-3-iodo pyridinium. At pH = 7.4, both risedronate and the phenylethane bisphosphonate bind in an enthalpy-driven manner (DeltaH approximately -9 to 10 kcal mol-1), but the other four bisphosphonates bind in an entropy-driven manner (DeltaS varying from 31.2 to 55.1 cal K-1 mol-1). However, at pH = 8.5, zoledronate binding switches from entropy to enthalpy-driven. The DeltaG results are highly correlated with FPPS inhibition results obtained using a radiochemical assay (R2 = 0.85, N = 11, P < 0.001). The DeltaH and DeltaS results are interpreted in terms of a model in which bisphosphonates with charged side chains have positive DeltaH values, due to the enthalpic cost of desolvation (due to strong ion-dipole interactions) and, likewise, a positive DeltaS, due to an increase in water entropy (both ligand and protein associated) on ligand binding to FPPS: the hydrop...Continue Reading

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Citations

Sep 4, 2012·Journal of Molecular Modeling·Masoud ArabiehMohammad Ghannadi-Maragheh
Mar 25, 2009·Journal of the American Chemical Society·Yonghui ZhangEric Oldfield
Jun 6, 2009·Journal of the American Chemical Society·Sujoy MukherjeeEric Oldfield
Jun 15, 2010·Chemical Communications : Chem Comm·Jinbo GaoDing Li
Mar 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Joo Hwan NoEric Oldfield
Nov 1, 2013·Chemical & Pharmaceutical Bulletin·Yuko KawasakiYutaka Hirakura
May 3, 2014·PLoS Pathogens·Na ShangRey-Ting Guo
Jan 31, 2007·Biological Chemistry·Daniela MollFriedrich W Herberg
Jul 22, 2008·Journal of Controlled Release : Official Journal of the Controlled Release Society·Mohiuddin A QuadirRainer Haag
Feb 19, 2009·Clinical Endocrinology·Bart L Clarke
Jun 18, 2015·Journal of Computer-aided Molecular Design·David FernándezJuan Frau
Apr 30, 2015·Physical Chemistry Chemical Physics : PCCP·Mitra AshouriM H Karimi-Jafari
Oct 4, 2012·Chemical Society Reviews·Satish Balasaheb Nimse, Taisun Kim
Jun 1, 2011·Chemistry, an Asian Journal·Susana GordoErnest Giralt
Mar 12, 2015·Acta Crystallographica. Section D, Biological Crystallography·Jason W SchmidbergerGunter Schneider
Jun 26, 2018·Langmuir : the ACS Journal of Surfaces and Colloids·Abshar HasanLalit M Pandey
Oct 11, 2012·ACS Medicinal Chemistry Letters·Guobin CaiYongcheng Song
Feb 14, 2012·Organometallics·Sung Ok KangEric V Anslyn

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