QM Study on the Mechanism of Carbonic Anhydrase II Inhibition with Glycosylcoumarin as Non-Zinc Mediated Inhibitors from Thermodynamic View Point


  • Mina Ghiasi Department of Chemistry, Faculty of Physics & Chemistry, Alzahra University, 19835-389, Vanak, Tehran
  • Mina Seifi Department of Chemistry, Faculty of Physics & Chemistry, Alzahra University, 19835-389, Vanak, Tehran




Carbonic Anhydrase, glycosylcoumarin, inhibition mechanism, Density functional theory, explicit solvent method


Carbonic anhydrase is an enzyme which has the zinc as the metallic part of it. This enzyme catalyzes the reversible reaction of turning carbon dioxide into bicarbonate. In this research the mechanism of inhibition a new class of inhibitor of this enzyme, glycosyl coumarin has been modeled using the density functional theory (DFT). First, the most constant confirmer of this four coumarin sugar derivatives which includes galactose, mannose, ribose and glucose has been selected and then they had been interacted as inhibitor with CA (II) enzyme’s active site. In further for showing the effect of sugar in these molecules, coumarin itself had been chosen as inhibitor and the inhibitory effect is surveyed. All calculations have been done by density functional theory in level of B3LYP with basic set 6-31G* and with Minnesota function M06 with basic set 6-31+G*.Thermodynamic functions like enthalpy of formation, entropy of formation and Gibbs free energy for CA-inhibitor have been computed. The results indicate that the reaction among these groups of inhibitors and Carbonic anhydrase is not of the type of direct and syndetic but the enzyme is deactivated with space effect and addition to this, the computed thermodynamic functions show that although this coumarin sugar derives have deterrence in the range of micro molar but, coumarin without sugar is a stronger deterrence for CA II. Finally, the interaction between the most constant confirmer (galactose coumarin) is surveyed as the best deterrence using the explicit solvent method.


[1] Supuran CT. Carbonic anhydrase inhibition with natural products: novel chemotypes and inhibition mechanisms. Mol Divers 2011; 15: 305-16.
[2] Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 2008; 7: 168-81.
[3] Xu Y, Feng L, Jeffrey PD, Shi Y, Morel FM. Structure and metal exchange in the cadmium carbonic anhydrase of marine diatoms. Nat Hum Behav 2008; 452: 56-61.
[4] Moya A, Tambutté S, Bertucci A, et al. Carbonic anhydrase in the scleractinian coral Stylophora pistillata characterization, localization, and role in biomineralization. J Biol Chem 2008; 283: 25475-84.
[5] Nishimori I, Onishi S, Takeuchi H, Supuran CT. The ? and ? classes carbonic anhydrases from Helicobacter pylori as novel drug targets. Curr Pharm Des 2008; 14: 622-30.
[6] Švastová E, Hul??ková A, Rafajová M, et al. Hypoxia activates the capacity of tumor?associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 2004; 577: 439-45.
[7] Ebbesen P, Pettersen EO, Gorr TA, et al. Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies. J Enzyme Inhib Med Chem 2009; 24: 1-39.
[8] Supuran CT, Scozzafava A, Casini A. Carbonic anhydrase inhibitors. Med Res Rev 2003; 23: 146-89.
[9] Supuran CT. Carbonic anhydrases-an overview. Curr Pharm Des 2008; 14: 603-14.
[10] Rowlett RS. Structure and catalytic mechanism of the ?-carbonic anhydrases. Biochim Biophys Acta 2010; 1804: 362-73.
[11] Zimmerman SA, Ferry JG, Supuran CT. Inhibition of the archaeal ?-class (Cab) and ?-class (Cam) carbonic anhydrases. Curr Top Med Chem 2007; 7: 901-8.
[12] Monti SM, Supuran CT, De Simone G. Anticancer carbonic anhydrase inhibitors: a patent review (2008–2013). Expert Opin Ther Pat 2013; 23: 737-49.
[13] Venters RA, Farmer II BT, Fierke CA, Spicer LD. Characterizing the use of perdeuteration in NMR studies of large proteins: 13 C, 15 N and 1 H assignments of human carbonic anhydrase II. J Mol Biol 1996; 264: 1101-16.
[14] Supuran CT. Carbonic anhydrase inhibitors: an editorial. Expert Opin Ther Pat 2013; 23: 677-9.
[15] Supuran CT, Maresca A, Gregá? F, Remko M. Three new aromatic sulfonamide inhibitors of carbonic anhydrases I, II, IV and XII. J Enzyme Inhib Med Chem 2013; 28: 289-93.
[16] Neri D, Supuran CT. Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 2011; 10: 767-77.
[17] Thiry A, Dogne JM, Masereel B, Supuran CT. Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Trends Pharmacol Sci 2006; 27: 566-73.
[18] Supuran CT. Carbonic anhydrase inhibitors and activators for novel therapeutic applications. Future Med Chem 2011; 3: 1165-80.
[19] Maresca A, Temperini C, Vu H, et al. Non-Zinc Mediated Inhibition of Carbonic Anhydrases: Coumarins Are a New Class of Suicide Inhibitors#. J Am Chem Soc 2009; 131: 3057-62.
[20] Maresca A, Temperini C, Pochet L, Masereel B, Scozzafava A, Supuran CT. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J Med Chem 2009; 53: 335-44.
[21] (a) Maresca A, Supuran CT. Coumarins incorporating hydroxy-and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II. Bioorg Med Chem Lett 2010; 20: 4511-4.
(b) Maresca A, Scozzafava A, Supuran CT. 7, 8-Disubstituted-but not 6, 7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range. Bioorg Med Chem Lett 2010; 20: 7255-8.
[22] Bonneau A, Maresca A, Winum JY, Supuran CT. Metronidazole-coumarin conjugates and 3-cyano-7-hydroxy-coumarin act as isoform-selective carbonic anhydrase inhibitors. J Enzyme Inhib Med Chem 2013; 28: 397-401.
[23] Touisni N, Maresca A, McDonald PC, et al. Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors. J Med Chem 2011; 54: 8271-7.
[24] Wagner J, Avvaru BS, Robbins AH, Scozzafava A, Supuran CT, McKenna R. Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations. Bioorg Med Chem 2010; 18: 4873-8.
[25] Spicer SS, Ge ZH, Tashian RE, Hazen?Martin DJ, Schulte BA. Comparative distribution of carbonic anhydrase isozymes III and II in rodent tissues. Am J Anat 1990; 187: 55-64.
[26] MJ Frisch, GW Trucks, HB Schlegel, GE Scuseria, et al. Gaussian. Inc., Wallingford CT. 2009.
[27] Dennington RD, Keith TA, Millam JM. GaussView 5.0. 8. Gaussian Inc. 2008.
[28] Parr RG, Yang W. Density Functional Theory of Atoms and Molecules Oxford Univ. Press, New York. 1989.
[29] Becke AD. Density?functional thermochemistry. III. The role of exact exchange. J Chem Phys 1993; 98: 5648-52.
[30] Zhao Y, Truhlar DG. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc 2008; 120: 215-41.
[31] Navarrete M, Rangel C, Corchado JC, Espinosa-Garcia J. Trapping of the OH radical by ?-tocopherol: a theoretical study. J Phys Chem A 2005; 109: 4777-84.
[32] Chandra AK, Uchimaru T. The OH bond dissociation energies of substituted phenols and proton affinities of substituted phenoxide ions: A DFT study. Int J Mol Sci 2002; 3: 407-22.
[33] Zhang HY, Ji HF. S–H proton dissociation enthalpies of thiophenolic cation radicals: a DFT study. J Mol Struct 2003; 663: 167-74.






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