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Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.

Steuber H, Heine A, Podjarny A, Klebe G
J Mol Biol 379 991-1016 (2008)
Related entries: 2pd5, 2pd9, 2pdb, 2pdc, 2pdf, 2pdg, 2pdh, 2pdi, 2pdj, 2pdk, 2pdl, 2pdm, 2pdn, 2pdp, 2pdq, 2pdu, 2pdx, 2pdy

Cited: 20 times
EuropePMC logo PMID: 18495158

Abstract

Inhibition of human aldose reductase (ALR2) evolved as a promising therapeutic concept to prevent late complications of diabetes. As well as appropriate affinity and bioavailability, putative inhibitors should possess a high level of selectivity for ALR2 over the related aldehyde reductase (ALR1). We investigated the selectivity-determining features by gradually mapping the residues deviating between the binding pockets of ALR1 and ALR2 into the ALR2 binding pocket. The resulting mutational constructs of ALR2 (eight point mutations and one double mutant) were probed for their influence towards ligand selectivity by X-ray structure analysis of the corresponding complexes and isothermal titration calorimetry (ITC). The binding properties of these mutants were evaluated using a ligand set of zopolrestat, a related uracil derivative, IDD388, IDD393, sorbinil, fidarestat and tolrestat. Our study revealed induced-fit adaptations within the mutated binding site as an essential prerequisite for ligand accommodation related to the selectivity discrimination of the ligands. However, our study also highlights the limits of the present understanding of protein-ligand interactions. Interestingly, binding site mutations not involved in any direct interaction to the ligands in various cases show significant effects towards their binding thermodynamics. Furthermore, our results suggest the binding site residues deviating between ALR1 and ALR2 influence ligand affinity in a complex interplay, presumably involving changes of dynamic properties and differences of the solvation/desolvation balance upon ligand binding.

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  1. Implication of crystal water molecules in inhibitor binding at ALR2 active site. Hymavati, Kumar V, Sobhia ME. Comput Math Methods Med 2012 541594 (2012)


Reviews citing this publication (6)

  1. The aldo-keto reductase superfamily and its role in drug metabolism and detoxification. Barski OA, Tipparaju SM, Bhatnagar A. Drug Metab Rev 40 553-624 (2008)
  2. Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment. Huang L, He R, Luo W, Zhu YS, Li J, Tan T, Zhang X, Hu Z, Luo D. Recent Pat Anticancer Drug Discov 11 184-196 (2016)
  3. Survey of the year 2008: applications of isothermal titration calorimetry. Falconer RJ, Penkova A, Jelesarov I, Collins BM. J Mol Recognit 23 395-413 (2010)
  4. Development of aldose reductase inhibitors for the treatment of inflammatory disorders. Chatzopoulou M, Pegklidou K, Papastavrou N, Demopoulos VJ. Expert Opin Drug Discov 8 1365-1380 (2013)
  5. Is there a link between selectivity and binding thermodynamics profiles? Tarcsay Á, Keserű GM. Drug Discov Today 20 86-94 (2015)
  6. Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition. Ruiz FX, Parés X, Farrés J. Metabolites 11 865 (2021)

Articles citing this publication (13)

  1. Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design. Cousido-Siah A, Ruiz FX, Mitschler A, Porté S, de Lera ÁR, Martín MJ, Manzanaro S, de la Fuente JA, Terwesten F, Betz M, Klebe G, Farrés J, Parés X, Podjarny A. Acta Crystallogr D Biol Crystallogr 70 889-903 (2014)
  2. In silico and in vitro studies of lupeol and iso-orientin as potential antidiabetic agents in a rat model. Malik A, Jamil U, Butt TT, Waquar S, Gan SH, Shafique H, Jafar TH. Drug Des Devel Ther 13 1501-1513 (2019)
  3. Structural and kinetic characterization of a maize aldose reductase. de Sousa SM, Rosselli LK, Kiyota E, da Silva JC, Souza GH, Peroni LA, Stach-Machado DR, Eberlin MN, Souza AP, Koch KE, Arruda P, Torriani IL, Yunes JA. Plant Physiol Biochem 47 98-104 (2009)
  4. Correlation of binding constants and molecular modelling of inhibitors in the active sites of aldose reductase and aldehyde reductase. Carbone V, Zhao HT, Chung R, Endo S, Hara A, El-Kabbani O. Bioorg Med Chem 17 1244-1250 (2009)
  5. X-ray structure of the V301L aldo-keto reductase 1B10 complexed with NADP(+) and the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity. Ruiz FX, Cousido-Siah A, Mitschler A, Farrés J, Parés X, Podjarny A. Chem Biol Interact 202 178-185 (2013)
  6. Structural Determinants of the Selectivity of 3-Benzyluracil-1-acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10. Ruiz FX, Cousido-Siah A, Porté S, Domínguez M, Crespo I, Rechlin C, Mitschler A, de Lera ÁR, Martín MJ, de la Fuente JÁ, Klebe G, Parés X, Farrés J, Podjarny A. ChemMedChem 10 1989-2003 (2015)
  7. Decreasing acidity in a series of aldose reductase inhibitors: 2-Fluoro-4-(1H-pyrrol-1-yl)phenol as a scaffold for improved membrane permeation. Chatzopoulou M, Patsilinakos A, Vallianatou T, Prnova MS, Zakelj S, Ragno R, Stefek M, Kristl A, Tsantili-Kakoulidou A, Demopoulos VJ. Bioorg Med Chem 22 2194-2207 (2014)
  8. B-factor Analysis and Conformational Rearrangement of Aldose Reductase. Balendiran GK, Pandian JR, Drake E, Vinayak A, Verma M, Cascio D. Curr Proteomics 11 151-160 (2014)
  9. Improvement in predicting drug sensitivity changes associated with protein mutations using a molecular dynamics based alchemical mutation method. Ono F, Chiba S, Isaka Y, Matsumoto S, Ma B, Katayama R, Araki M, Okuno Y. Sci Rep 10 2161 (2020)
  10. Design, synthesis and evaluation of rhodanine derivatives as aldose reductase inhibitors. Agrawal YP, Agrawal MY, Gupta AK. Chem Biol Drug Des 85 172-180 (2015)
  11. Radiation damage reveals promising interaction position. Koch C, Heine A, Klebe G. J Synchrotron Radiat 18 782-789 (2011)
  12. Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase? Sandner A, Ngo K, Sager CP, Scheer F, Daude M, Diederich WE, Heine A, Klebe G. Biomolecules 11 1837 (2021)
  13. 6D-QSAR for predicting biological activity of human aldose reductase inhibitors using quasar receptor surface modeling. Sokouti B, Hamzeh-Mivehroud M. BMC Chem 17 63 (2023)


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