Tracing Changes in Protonation: A Prerequisite to Factorize Thermodynamic Data of Inhibitor Binding to Aldose Reductase

Steuber, H.; Czodrowski, Paul; Sotriffer, Christoph A.; Klebe, G.

doi:10.1016/j.jmb.2007.08.063

Cited by 45 publications

(49 citation statements)

References 50 publications

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“…Overview of the thermodynamic data of the different complexes. WT388 has been determined elsewhere 18 Data are not corrected for superimposed heat of ionization resulting from a change in protonation state. Very similar superimposed effects will be given for all considered complexes.…”

Section: Discussionmentioning

confidence: 99%

“…The binding characteristics of IDD 388 to wildtype hAR have previously been determined; 18 for comparison, the binding contributions of WT594 have been collected in this study. A buffer dependence resulting from a change in the protonation state of Tyr48 in the catalytic center had been observed for IDD 388 and IDD 594 binding.…”

Section: Characterization Of the Thermodynamic Binding Profilementioning

confidence: 99%

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Tracing the Detail: How Mutations Affect Binding Modes and Thermodynamic Signatures of Closely Related Aldose Reductase Inhibitors

Koch

Heine

Klebe

2011

Journal of Molecular Biology

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Section: Discussionmentioning

confidence: 99%

Section: Characterization Of the Thermodynamic Binding Profilementioning

confidence: 99%

Tracing the Detail: How Mutations Affect Binding Modes and Thermodynamic Signatures of Closely Related Aldose Reductase Inhibitors

Koch

Heine

Klebe

2011

Journal of Molecular Biology

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“…Therefore, a correction for an uptake of 0.6 mol of protons with a heat of ionization for Tris buffer of 48 kJ/mol is necessary. 19 Consequently, the exothermic proton uptake by the buffer contributes 28.8 kJ/mol to the observed enthalpy. Accordingly, for 3c, 3e and 3l the corrected enthalpy of binding ΔH bind 0 is in total balance 10.8 kJ/mol lower than the experimentally observed heat signal in Tris buffer.…”

Section: Itc Data Protonation Correctionmentioning

confidence: 97%

Non-additivity of Functional Group Contributions in Protein–Ligand Binding: A Comprehensive Study by Crystallography and Isothermal Titration Calorimetry

Baum¹,

Muley²,

Smolinski³

et al. 2010

Journal of Molecular Biology

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145

166

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“…A dual-target inhibitor that could simultaneously block GLOI and AR is likely to be more effective than a single-target GLOI inhibitor. GSH analog inhibitors are unlikely candidates for dual-target inhibitors because inhibition towards both GLOI and AR requires substituents with opposite polarities (hydrophobic and hydrophilic) on the thiol to bind to the active sites of GLOI and AR [3,30] . In fact, a carboxyl group is a typical (and critical) functional group for most known AR inhibitors [31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor

et al. 2015

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Aim: Glyoxalase I (GLOI), a glutathione (GSH)-dependent enzyme, is overexpressed in tumor cells and related to multi-drug resistance in chemotherapy, making GLOI inhibitors as potential anti-tumor agents. But the most studied GSH analogs exhibit poor pharmacokinetic properties. The aim of this study was to discover novel non-GSH analog GLOI inhibitors and analyze their binding mechanisms. Methods: Mouse GLOI (mGLOI) was expressed in BL21 (DE3) pLysS after induction with isopropyl-β-D-1-thiogalactopyranoside and purified using AKTA FPLC system. An in vitro mGLOI enzyme assay was used to screen a small pool of compounds containing carboxyl groups. Crystal structure of the mGLOI-inhibitor complex was determined at 2.3 Å resolution. Molecular docking study was performed using Discovery Studio 2.5 software package. Results: A natural compound 18-β-glycyrrhetinic acid (GA) and its derivative carbenoxolone were identified as potent competitive non-GSH analog mGLOI inhibitors with K i values of 0.29 μmol/L and 0.93 μmol/L, respectively. Four pentacyclic triterpenes (ursolic acid, oleanolic acid, betulic acid and tripterine) showed weak activities (mGLOI inhibition ratio <25% at 10 μmol/L) and other three (maslinic acid, corosolic acid and madecassic acid) were inactive. The crystal structure of the mGLOI-GA complex showed that the carboxyl group of GA mimicked the γ-glutamyl residue of GSH by hydrogen bonding to the glutamyl sites (residues Arg38B, Asn104B and Arg123A) in the GSH binding site of mGLOI. The extensive van der Waals interactions between GA and the surrounding residues also contributed greatly to the binding of GA and mGLOI. Conclusion: This work demonstrates a carboxyl group to be an important functional feature of non-GSH analog GLOI inhibitors.

show abstract

Tracing Changes in Protonation: A Prerequisite to Factorize Thermodynamic Data of Inhibitor Binding to Aldose Reductase

Cited by 45 publications

References 50 publications

Tracing the Detail: How Mutations Affect Binding Modes and Thermodynamic Signatures of Closely Related Aldose Reductase Inhibitors

Tracing the Detail: How Mutations Affect Binding Modes and Thermodynamic Signatures of Closely Related Aldose Reductase Inhibitors

Non-additivity of Functional Group Contributions in Protein–Ligand Binding: A Comprehensive Study by Crystallography and Isothermal Titration Calorimetry

Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor

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