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Structural analysis of charge discrimination in the binding of inhibitors to human carbonic anhydrases I and II.

Srivastava DK, Jude KM, Banerjee AL, Haldar M, Manokaran S, Kooren J, Mallik S, Christianson DW
J Am Chem Soc 129 5528-37 (2007)
Related entries: 2nmx, 2nn1, 2nn7, 2nng, 2nns, 2nnv

Cited: 30 times
EuropePMC logo PMID: 17407288

Abstract

Despite the similarity in the active site pockets of carbonic anhydrase (CA) isozymes I and II, the binding affinities of benzenesulfonamide inhibitors are invariably higher with CA II as compared to CA I. To explore the structural basis of this molecular recognition phenomenon, we have designed and synthesized simple benzenesulfonamide inhibitors substituted at the para position with positively charged, negatively charged, and neutral functional groups, and we have determined the affinities and X-ray crystal structures of their enzyme complexes. The para-substituents are designed to bind in the midsection of the 15 A deep active site cleft, where interactions with enzyme residues and solvent molecules are possible. We find that a para-substituted positively charged amino group is more poorly tolerated in the active site of CA I compared with CA II. In contrast, a para-substituted negatively charged carboxylate substituent is tolerated equally well in the active sites of both CA isozymes. Notably, enzyme-inhibitor affinity increases upon neutralization of inhibitor charged groups by amidation or esterification. These results inform the design of short molecular linkers connecting the benzenesulfonamide group and a para-substituted tail group in "two-prong" CA inhibitors: an optimal linker segment will be electronically neutral, yet capable of engaging in at least some hydrogen bond interactions with protein residues and/or solvent. Microcalorimetric data reveal that inhibitor binding to CA I is enthalpically less favorable and entropically more favorable than inhibitor binding to CA II. This contrasting behavior may arise in part from differences in active site desolvation and the conformational entropy of inhibitor binding to each isozyme active site.

Reviews - 2nno mentioned but not cited (1)

  1. Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding. Krishnamurthy VM, Kaufman GK, Urbach AR, Gitlin I, Gudiksen KL, Weibel DB, Whitesides GM. Chem Rev 108 946-1051 (2008)

Articles - 2nno mentioned but not cited (4)

  1. High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design. Sippel KH, Robbins AH, Domsic J, Genis C, Agbandje-McKenna M, McKenna R. Acta Crystallogr Sect F Struct Biol Cryst Commun 65 992-995 (2009)
  2. Structural analysis of charge discrimination in the binding of inhibitors to human carbonic anhydrases I and II. Srivastava DK, Jude KM, Banerjee AL, Haldar M, Manokaran S, Kooren J, Mallik S, Christianson DW. J Am Chem Soc 129 5528-5537 (2007)
  3. Atomic resolution studies of carbonic anhydrase II. Behnke CA, Le Trong I, Godden JW, Merritt EA, Teller DC, Bajorath J, Stenkamp RE. Acta Crystallogr D Biol Crystallogr 66 616-627 (2010)
  4. Survey of Predictors of Propensity for Protein Production and Crystallization with Application to Predict Resolution of Crystal Structures. Gao J, Wu Z, Hu G, Wang K, Song J, Joachimiak A, Kurgan L. Curr Protein Pept Sci 19 200-210 (2018)


Reviews citing this publication (4)

  1. Structure, function and applications of carbonic anhydrase isozymes. Imtaiyaz Hassan M, Shajee B, Waheed A, Ahmad F, Sly WS. Bioorg Med Chem 21 1570-1582 (2013)
  2. A survey of the year 2007 literature on applications of isothermal titration calorimetry. Bjelić S, Jelesarov I. J Mol Recognit 21 289-312 (2008)
  3. Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design. Linkuvienė V, Zubrienė A, Manakova E, Petrauskas V, Baranauskienė L, Zakšauskas A, Smirnov A, Gražulis S, Ladbury JE, Matulis D. Q Rev Biophys 51 e10 (2018)
  4. Module assembly for designing multivalent mid-sized inhibitors of protein-protein interactions. Ohkanda J. Chem Rec 13 561-575 (2013)

Articles citing this publication (21)

  1. Ligand-directed tosyl chemistry for protein labeling in vivo. Tsukiji S, Miyagawa M, Takaoka Y, Tamura T, Hamachi I. Nat Chem Biol 5 341-343 (2009)
  2. Bioluminescent sensor proteins for point-of-care therapeutic drug monitoring. Griss R, Schena A, Reymond L, Patiny L, Werner D, Tinberg CE, Baker D, Johnsson K. Nat Chem Biol 10 598-603 (2014)
  3. Cryptophane xenon-129 nuclear magnetic resonance biosensors targeting human carbonic anhydrase. Chambers JM, Hill PA, Aaron JA, Han Z, Christianson DW, Kuzma NN, Dmochowski IJ. J Am Chem Soc 131 563-569 (2009)
  4. Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies. Göksu S, Naderi A, Akbaba Y, Kalın P, Akıncıoğlu A, Gülçin İ, Durdagi S, Salmas RE. Bioorg Chem 56 75-82 (2014)
  5. Inhibition and binding studies of carbonic anhydrase isozymes I, II and IX with benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulphonamides. Baranauskienė L, Hilvo M, Matulienė J, Golovenko D, Manakova E, Dudutienė V, Michailovienė V, Torresan J, Jachno J, Parkkila S, Maresca A, Supuran CT, Gražulis S, Matulis D. J Enzyme Inhib Med Chem 25 863-870 (2010)
  6. Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action. Bonardi A, Nocentini A, Bua S, Combs J, Lomelino C, Andring J, Lucarini L, Sgambellone S, Masini E, McKenna R, Gratteri P, Supuran CT. J Med Chem 63 7422-7444 (2020)
  7. Thermodynamic optimisation in drug discovery: a case study using carbonic anhydrase inhibitors. Scott AD, Phillips C, Alex A, Flocco M, Bent A, Randall A, O'Brien R, Damian L, Jones LH. ChemMedChem 4 1985-1989 (2009)
  8. Analysis of a shortened form of human carbonic anhydrase VII expressed in vitro compared to the full-length enzyme. Bootorabi F, Jänis J, Smith E, Waheed A, Kukkurainen S, Hytönen V, Valjakka J, Supuran CT, Vullo D, Sly WS, Parkkila S. Biochimie 92 1072-1080 (2010)
  9. The first example of a significant active site conformational rearrangement in a carbonic anhydrase-inhibitor adduct: the carbonic anhydrase I-topiramate complex. Alterio V, Monti SM, Truppo E, Pedone C, Supuran CT, De Simone G. Org Biomol Chem 8 3528-3533 (2010)
  10. Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I, II, VII, XII and XIV. Gavernet L, Gonzalez Funes JL, Palestro PH, Bruno Blanch LE, Estiu GL, Maresca A, Barrios I, Supuran CT. Bioorg Med Chem 21 1410-1418 (2013)
  11. Synthesis and biological profile of new 1,2,3,4-tetrahydroisoquinolines as selective carbonic anhydrase inhibitors. Gitto R, Damiano FM, De Luca L, Ferro S, Vullo D, Supuran CT, Chimirri A. Bioorg Med Chem 19 7003-7007 (2011)
  12. On-chip fragment-based approach for discovery of high-affinity bivalent inhibitors. Miyazaki I, Simizu S, Ishida K, Osada H. Chembiochem 10 838-843 (2009)
  13. Virtual screening-driven identification of human carbonic anhydrase inhibitors incorporating an original, new pharmacophore. Pala N, Dallocchio R, Dessì A, Brancale A, Carta F, Ihm S, Maresca A, Sechi M, Supuran CT. Bioorg Med Chem Lett 21 2515-2520 (2011)
  14. Module assembly for protein-surface recognition: geranylgeranyltransferase I bivalent inhibitors for simultaneous targeting of interior and exterior protein surfaces. Machida S, Usuba K, Blaskovich MA, Yano A, Harada K, Sebti SM, Kato N, Ohkanda J. Chemistry 14 1392-1401 (2008)
  15. Binding affinity of substituted ureido-benzenesulfonamide ligands to the carbonic anhydrase receptor: a theoretical study of enzyme inhibition. Sahu C, Sen K, Pakhira S, Mondal B, Das AK. J Comput Chem 34 1907-1916 (2013)
  16. Excimer-monomer fluorescence changes by supramolecular disassembly for protein sensing and quantification. Liu H, Westley J, Thayumanavan S. Chem Commun (Camb) 57 9776-9779 (2021)
  17. Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors. Peerzada MN, Vullo D, Paoletti N, Bonardi A, Gratteri P, Supuran CT, Azam A. ACS Med Chem Lett 14 810-819 (2023)
  18. Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases. Sobati M, Abdoli M, Bonardi A, Gratteri P, Supuran CT, Žalubovskis R. ACS Med Chem Lett 14 1067-1072 (2023)
  19. Inhibition Studies on Human and Mycobacterial Carbonic Anhydrases with N-((4-Sulfamoylphenyl)carbamothioyl) Amides. Abdoli M, Bonardi A, Paoletti N, Aspatwar A, Parkkila S, Gratteri P, Supuran CT, Žalubovskis R. Molecules 28 4020 (2023)
  20. Stabilization of anionic and neutral forms of a fluorophoric ligand at the active site of human carbonic anhydrase I. Manokaran S, Banerjee J, Mallik S, Srivastava DK. Biochim Biophys Acta 1804 1965-1973 (2010)
  21. Supramolecular displacement-mediated activation of a silent fluorescence probe for label-free ligand screening. Torres DA, Azagarsamy MA, Thayumanavan S. J Am Chem Soc 134 7235-7237 (2012)


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