Skip to main content
SpringerLink
Log in

QM and QM/MM study on inhibition mechanism of polyphenolic compounds as non-classical inhibitors of α-human carbonic anhydrase (II)

  • Regular Article
  • Published:
Theoretical Chemistry Accounts Aims and scope Submit manuscript

Abstract

Phenolic and polyphenolic compounds are distributed in plant tissues as a secondary metabolite which are compromised in multiple and imperative physiological phenomena. Herein, inhibition mechanism of human carbonic anhydrase isoform II, hCAII, with seven phenolic compounds including phenol, catechol, resorcinol, 4-methyl catechol, vanillic acid, trans-cinnamic acid and ortho-coumaric acid has been investigated using quantum mechanical and ONIOM calculations. B3LYP-D3/6–311++G** method has been employed to calculate the electronic structure and electronic energy of different species through the reaction mechanism path. The model system of hCAVII has been used that includes the core of the catalytic center, Zn2+, binds to three histidine residues and a hydroxide ion or water molecule forming a first coordination shell. Thr199 and Glu106 were considered as neighboring residues to the ones binding zinc. All thermodynamic functions through the reaction path are evaluated in different phases. The calculated results indicate that all phenolic inhibitors do not directly interact with the zinc ion in the CA active center, and the presence of aromatic moieties was associated with more effective inhibition. In addition, the implicit and explicit solvent effect has been considered for water solvent using QM and ONIOM (QM/MM) calculations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Scheme 2
Scheme 3
Fig. 1
Scheme 4
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181

    Article  CAS  PubMed  Google Scholar 

  2. De Luca V, Petreni A, Nocentini A, Scaloni A, Supuran CT, Capasso C (2021) Effect of sulfonamides and their structurally related derivatives on the activity of ι-carbonic anhydrase from Burkholderia territorii. Int J Mol Sci 22(2):571

    Article  PubMed Central  CAS  Google Scholar 

  3. Petreni A, De Luca V, Scaloni A, Nocentini A, Capasso C, Supuran CT (2021) Anion inhibition studies of the Zn (II)-bound ι-carbonic anhydrase from the Gram-negative bacterium Burkholderia territorii. J Enzyme Inhib Med Chem 36(1):372–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jin S, Vullo D, Bua S, Nocentini A, Supuran CT, Gao YG (2020) Structural and biochemical characterization of novel carbonic anhydrases from Phaeodactylum tricornutum. Acta Crystallogr D 76(7):676–686

    Article  CAS  Google Scholar 

  5. Ghiasi M, Gholami S, Nasiri S (2021) QM study of carbon dioxide (CO2) and carbonyl sulfide (COS) degradation by cluster model of Carbonic anhydrase enzyme. Comput Theor Chem 1199:113188

    Article  CAS  Google Scholar 

  6. Miscione GP, Stenta M, Spinelli D, Anders E, Bottoni A (2007) New computational evidence for the catalytic mechanism of carbonic anhydrase. Theor Chem Acc 118(1):193–201

    Article  CAS  Google Scholar 

  7. Murcko MA (1997) Conformational analysis of carbonic anhydrase inhibitors using ab initio molecular orbital methods. 1. Rotational isomerism in methane sulfonamide anion, CH3-SO2-NH−. Theor Chem Acc 96(1):56–60

    Article  CAS  Google Scholar 

  8. Krishnamurthy VM, Kaufman GK, Urbach AR, Gitlin I, Gudiksen KL, Weibel DB, Whitesides GM (2008) Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein−ligand binding. Chem Rev 108(3):946–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fares M, Eldehna WM, Bua S, Lanzi C, Lucarini L, Masini E, Peat TS, Abdel-Aziz HA, Nocentini A, Keller PA, Supuran CT (2020) Discovery of potent dual-tailed benzenesulfonamide inhibitors of human carbonic anhydrases implicated in glaucoma and in vivo profiling of their intraocular pressure-lowering action. J Med Chem 63(6):3317–3326

    Article  CAS  PubMed  Google Scholar 

  10. Nocentini A, Moi D, Deplano A, Osman SM, AlOthman ZA, Balboni G, Supuran CT, Onnis V (2020) Sulfonamide/sulfamate switch with a series of piperazinylureido derivatives: Synthesis, kinetic and in silico evaluation as carbonic anhydrase isoforms I, II, IV, and IX inhibitors. Eur J Med Chem 186:111896

    Article  CAS  PubMed  Google Scholar 

  11. Yamali C, Gul HI, Kazaz C, Levent S, Gulcin I (2020) Synthesis, structure elucidation, and in vitro pharmacological evaluation of novel polyfluoro substituted pyrazoline type sulfonamides as multi-target agents for inhibition of acetylcholinesterase and carbonic anhydrase I and II enzymes. Bioorgan Chem 96:103627

    Article  CAS  Google Scholar 

  12. Abdel-Mohsen HT, El Kerdawy AM, Omar MA, Berrino E, Abdelsamie AS, El Diwani HI, Supuran CT (2020) New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis, in vitro biological evaluation, and molecular docking studies. Bioorg Med Chem 28(5):115329

    Article  CAS  PubMed  Google Scholar 

  13. Gavernet L, Cisneros HSS, Bruno-Blanch LE, Estiú GL (2003) Synthesis of anticonvulsant sulfamides. Theoretical study of the related mechanism. Theor Chem Acc 110(6):434–440

    Article  CAS  Google Scholar 

  14. Veale CG, Mateos Jimenez M, Mackay CL, Clarke DJ (2020) Native ion mobility mass spectrometry reveals that small organic acid fragments impart gas-phase stability to carbonic anhydrase II. Rapid Commun Mass Spectrom 34(2):e8570

    Article  CAS  PubMed  Google Scholar 

  15. Krasavin M, Kalinin S, Zozulya S, Griniukova A, Borysko P, Angeli A, Supuran CT (2020) Further validation of strecker-type α-aminonitriles as a new class of potent human carbonic anhydrase II inhibitors: hit expansion within the public domain using differential scanning fluorimetry leads to chemotype refinement. J Enzyme Inhib Med Chem 35(1):165–171

    Article  CAS  PubMed  Google Scholar 

  16. Remigante A, Morabito R, Marino A (2020) Natural antioxidants beneficial effects on anion exchange through band 3 protein in human erythrocytes. Antioxidants 9(1):25

    Article  CAS  Google Scholar 

  17. Wu S, Chen J, Ma L, Zhang K, Wang X, Wei Y, Xu J, Xu X (2020) Design of carbonic anhydrase with improved thermostability for CO2 capture via molecular simulations. J CO2 Util 38:141–147

    Article  CAS  Google Scholar 

  18. Tanini D, Ricci L, Capperucci A, Mannelli LD, Ghelardini C, Peat TS, Carta F, Angeli A, Supuran CT (2019) Synthesis of novel tellurides bearing benzensulfonamide moiety as carbonic anhydrase inhibitors with antitumor activity. Eur J Med Chem 181:111586

    Article  PubMed  CAS  Google Scholar 

  19. Said MA, Eldehna WM, Nocentini A, Fahim SH, Bonardi A, Elgazar AA, Kryštof V, Soliman DH, Abdel-Aziz HA, Gratteri P, Abou-Seri SM, Supuran CT (2020) Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: design, synthesis, and in vitro biological evaluation. Eur J Med Chem 189:112019

    Article  CAS  PubMed  Google Scholar 

  20. Ghiasi M, Kamalinahad S, Arabieh M, Zahedi M (2012) Carbonic anhydrase inhibitors: a quantum mechanical study of interaction between some antiepileptic drugs with active center of carbonic anhydrase enzyme. Comput Theor Chem 992:59–69

    Article  CAS  Google Scholar 

  21. Supuran CT (2008) Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. Curr Pharmaceut Des 14(7):641–648

    Article  CAS  Google Scholar 

  22. Sarikaya SBÖ, Topal F, Şentürk M, Gülçin I, Supuran CT (2011) In vitro inhibition of α-carbonic anhydrase isozymes by some phenolic compounds. Bioorg Med Chem Lett 21(14):4259–4262

    Article  CAS  Google Scholar 

  23. Davis RA, Hofmann A, Osman A, Hall RA, Mühlschlegel FA, Vullo D, Innocenti A, Supuran CT, Poulsen SA (2011) Natural product-based phenols as novel probes for mycobacterial and fungal carbonic anhydrases. J Med Chem 54(6):1682–1692

    Article  CAS  PubMed  Google Scholar 

  24. Gulcin I, Beydemir S (2013) Phenolic compounds as antioxidants: carbonic anhydrase isoenzymes inhibitors. Mini Rev Med Chem 13(3):408–430

    CAS  PubMed  Google Scholar 

  25. Sentürk M, Gülçin I, Daştan A, Küfrevioğlu OI, Supuran CT (2009) Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols. Bioorgan Med Chem 17(8):3207–3211

    Article  CAS  Google Scholar 

  26. Ghiasi M, Seifi M (2017) Thermodynamic study on the mechanism of carbonic anhydrase XII inhibition with glycosyl coumarin as non-zinc mediated inhibitors: A quantum mechanical investigation. Comput Theor Chem 1118:16–25

    Article  CAS  Google Scholar 

  27. Ghiasi M, Gholami S (2020) Quantum mechanical study of human carbonic anhydrase II incomplex with polyamines as novel inhibitors: kinetic and thermodynamic investigation. Comput Theor Chem 1186:112911

    Article  CAS  Google Scholar 

  28. Carta F, Temperini C, Innocenti A, Scozzafava A, Kaila K, Supuran CT (2010) Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule. J Med Chem 53(15):5511–5522

    Article  CAS  PubMed  Google Scholar 

  29. Kamran Khan M, Huma ZE, Dangles OA (2014) Comprehensive review on flavanones, the major citrus polyphenols. J Food Compost Anal 33(1):85–104

    Article  CAS  Google Scholar 

  30. D’Ambrosio K, Carradori S, Cesa S, Angeli A, Monti SM, Supuran CT, De Simone G (2020) Catechols: a new class of carbonic anhydrase inhibitors. Chem Comm 56(85):13033–13036

    Article  CAS  PubMed  Google Scholar 

  31. Nocentini A, Osman SM, Del Prete S, Capasso C, ALOthman ZA, Supuran CT (2019) Extending the γ-class carbonic anhydrases inhibition profiles with phenolic compounds. Bioorg Chem 93:103336

    Article  CAS  PubMed  Google Scholar 

  32. Innocenti A, Gülçin I, Scozzafava A, Supuran CT (2010) Carbonic anhydrase inhibitors. Antioxidant polyphenols effectively inhibit mammalian isoforms I–XV. Bioorg Med Chem Lett 20(17):5050–5053

    Article  CAS  PubMed  Google Scholar 

  33. Scozzafava A, Passaponti M, Supuran CT, Gülçin İ (2015) Carbonic anhydrase inhibitors: guaiacol and catechol derivatives effectively inhibit certain human carbonic anhydrase isoenzymes (hCA I, II, IX and XII). J Enzyme Inhib Med Chem 30(4):586–591

    Article  CAS  PubMed  Google Scholar 

  34. Beyza Öztürk Sarıkaya S, Gülçin İ, Supuran CT (2010) Carbonic anhydrase inhibitors: inhibition of human erythrocyte isozymes I and II with a series of phenolic acids. Chem Biol Drug Design 75(5):515–520

    Article  CAS  Google Scholar 

  35. Nair SK, Ludwig PA, Christianson DW (1994) Two-site binding of phenol in the active site of human carbonic anhydrase II: structural implications for substrate association. J Am Chem Soc 116(8):3659–3660

    Article  CAS  Google Scholar 

  36. Maresca A, Temperini C, Pochet L, Masereel B, Scozzafava A, Supuran CT (2010) Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J Med Chem 53(1):335–344

    Article  CAS  PubMed  Google Scholar 

  37. De Simone G, Bua S, Supuran CT, Alterio V (2021) Benzyl alcohol inhibits carbonic anhydrases by anchoring to the zinc coordinated water molecule. Biochem Biophys Res Commun 548:217–221

    Article  PubMed  CAS  Google Scholar 

  38. Blomberg MR, Borowski T, Himo F, Liao RZ, Siegbahn PE (2014) Quantum chemical studies of mechanisms for metalloenzymes. Chem Rev 114(7):3601–3658

    Article  CAS  PubMed  Google Scholar 

  39. Lonsdale R, Mulholland AJ (2014) QM/MM modelling of drug-metabolizing enzymes. Curr Top Med Chem 14(11):1339–1347

    Article  CAS  PubMed  Google Scholar 

  40. Sousa SF, Ribeiro AJ, Neves RP, Brás NF, Cerqueira NM, Fernandes PA, Ramos MJ (2017) Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms. Wiley Interdiscip Rev Comput Mol Sci 7(2):e1281

    Article  CAS  Google Scholar 

  41. Świderek K, Tuñón I, Moliner V, Bertran J (2015) Computational strategies for the design of new enzymatic functions. Arch Biochem Biophys 582:68–79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Warshel A (2014) Multiscale modeling of biological functions: from enzymes to molecular machines (Nobel Lecture). Angew Chem Int Ed 53(38):10020–10031

    Article  CAS  Google Scholar 

  43. Piazzetta P, Marino T, Russo N (2014) Promiscuous ability of human carbonic anhydrase: QM and QM/MM investigation of carbon dioxide and carbodiimide hydration. Inorg Chem 53(7):3488–3493

    Article  CAS  PubMed  Google Scholar 

  44. Karioti A, Carta F, Supuran CT (2016) Phenols and polyphenols as carbonic anhydrase inhibitors. Molecules 21(12):1649

    Article  CAS  PubMed Central  Google Scholar 

  45. Martins CF, Neves LA, Estevão M, Rosatella A, Alves VD, Afonso CA, Crespo JG, Coelhoso IM (2016) Effect of water activity on carbon dioxide transport in cholinium-based ionic liquids with carbonic anhydrase. Sep Purif Technol 168:74–82

    Article  CAS  Google Scholar 

  46. Supuran CT (2016) Structure and function of carbonic anhydrases. Biochem J 473(14):2023–2032

    Article  CAS  PubMed  Google Scholar 

  47. Amata O, Marino T, Russo N, Toscano M (2011) Catalytic activity of a ζ-class zinc and cadmium containing carbonic anhydrase. Compared work mechanisms. Phys Chem Chem Phys 13(8):3468–3477

    Article  CAS  PubMed  Google Scholar 

  48. Liao RZ, Yu JG, Himo F (2010) Reaction mechanism of the trinuclear zinc enzyme phospholipase C: a density functional theory study. J Phys Chem B 114(7):2533–2540

    Article  CAS  PubMed  Google Scholar 

  49. Marino T, Russo N, Toscano M (2013) Catalytic mechanism of the arylsulfatase promiscuous enzyme from Pseudomonas aeruginosa. Chem Eur J 19(6):2185–2192

    Article  CAS  PubMed  Google Scholar 

  50. Ramos MJ, Fernandes PA (2008) Computational enzymatic catalysis. Acc Chem Res 41(6):689–698

    Article  CAS  PubMed  Google Scholar 

  51. Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J Chem Phys 132(15):154104

    Article  PubMed  CAS  Google Scholar 

  52. Antony J, Grimme S, Liakos DG, Neese F (2011) Protein–ligand interaction energies with dispersion corrected density functional theory and high-level wave function based methods. J Phys Chem A 115(41):11210–11220

    Article  CAS  PubMed  Google Scholar 

  53. Boys SF, Bernardi FJMP (1970) The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol Phys 19(4):553–566

    Article  CAS  Google Scholar 

  54. Vreven T, Morokuma K (2006) Chapter 3 Hybrid Methods: ONIOM(QM:MM) and QM/MM. Annu Rep Comput Chem 2:35–51

    Article  CAS  Google Scholar 

  55. Chung LW, Sameera WM, Ramozzi R, Page AJ, Hatanaka M, Petrova GP, Harris TV, Li X, Ke Z, Liu F, Li HB, Morokuma K (2015) The ONIOM method and its applications. Chem Rev 115(12):5678–5796

    Article  CAS  PubMed  Google Scholar 

  56. Mennucci B, Cammi R (2008) Continuum solvation models in chemical physics: from theory to applications. Wiley, Chichester, p 1

    Google Scholar 

  57. Orozco M, Luque FJ (2000) Theoretical methods for the description of the solvent effect in biomolecular systems. Chem Rev 100(11):4187–4226

    Article  CAS  PubMed  Google Scholar 

  58. Ghiasi M, Shahabi P, Supuran CT (2021) Quantum mechanical study on the activation mechanism of human carbonic anhydrase VII cluster model with bis-histamine Schiff bases and bis-spinaceamine derivatives. Bioorg Med Chem 44:116276

    Article  CAS  PubMed  Google Scholar 

  59. Ghiasi M, Bavafa S, Zahedi M (2021) QM study of interaction between arginine amino acid and Au clusters and the effects on arginine acidity. Gold Bull 54(1):45–57

    Article  CAS  Google Scholar 

  60. Xu Y, Feng L, Jeffrey PD, Shi Y, Morel FM (2008) Structure and metal exchange in the cadmium carbonic anhydrase of marine diatoms. Nature 452:56–61

    Article  CAS  PubMed  Google Scholar 

  61. Kimber MS, Pai EF (2000) The active site architecture of Pisum sativum β-carbonic anhydrase is a mirror image of that of α-carbonic anhydrases. EMBO J 19:1407–1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Amata O, Marino T, Russo N, Toscano M (2009) Human insulin-degrading enzyme working mechanism. J Am Chem Soc 131:14804–14811

    Article  CAS  PubMed  Google Scholar 

  63. Amata O, Marino T, Russo N, Toscano M (2011) A proposal for mitochondrial processing peptidase catalytic mechanism. J Am Chem Soc 133:17824–17831

    Article  CAS  PubMed  Google Scholar 

  64. Siegbahn PE, Himo F (2009) Recent developments of the quantum chemical cluster approach for modeling enzyme reactions. J Biol Inorg Chem 14:643–651

    Article  CAS  PubMed  Google Scholar 

  65. Siegbahn PE, Himo F (2011) The quantum chemical cluster approach for modeling enzyme reactions. Wiley Interdiscip Rev Comput Mol Sci 1:323–336

    Article  CAS  Google Scholar 

  66. Marino T, Russo N, Toscano M (2005) A comparative study of the catalytic mechanisms of the zinc and cadmium containing carbonic anhydrase. J Am Chem Soc 127:4242–4253

    Article  CAS  PubMed  Google Scholar 

  67. Miertuš S, Scrocco E, Tomasi J (1981) Electrostatic interaction of a solute with a continuum. A direct utilizaion of AB initio molecular potentials for the prevision of solvent effects. Chem Phys 55(1):117–129

    Article  Google Scholar 

  68. Miertus S, Tomasi J (1982) Approximate evaluations of the electrostatic free energy and internal energy changes in solution processes. Chem Phys 65(2):239–245

    Article  CAS  Google Scholar 

  69. Pascual-Ahuir JL, Silla E, Tomasi J, Bonaccorsi R (1987) Electrostatic interaction of a solute with a continuum. Improved description of the cavity and of the surface cavity bound charge distribution. J Comput Chem 8(6):778–787

    Article  CAS  Google Scholar 

  70. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JJA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA, Gaussian 09 (2009) Revision D. 01, Gaussian Inc, Wallingford

  71. Sahin H, Can Z, Yildiz O, Kolayli S, Innocenti A, Scozzafava G, Supuran CT (2012) Inhibition of carbonic anhydrase isozymes I and II with natural products extracted from plants, mushrooms and honey. J Enzyme Inhib Med Chem 27(3):395–402

    Article  CAS  PubMed  Google Scholar 

  72. Tibell L, Forsman C, Simonsson I, Lindskog S (1985) The inhibition of human carbonic anhydrase II by some organic compounds. Biochim Biophys Acta 829(2):202–208

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge financial support from the research council of Alzahra University.

Author information

Authors and Affiliations

  1. Department of Chemistry, Faculty of Physics and Chemistry, Alzahra University, Tehran, Iran

    Mina Ghiasi, Nasrin Emami Goli & Samira Gholami

  2. Dipartimento Neurofarba, Sezione di, Scienze Farmaceutiche e Nutraceutiche, Universita degli Studi di Firenze, Sesto Fiorentino, Italy

    Claudiu T. Supuran

Authors
  1. Mina Ghiasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nasrin Emami Goli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samira Gholami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claudiu T. Supuran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mina Ghiasi.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghiasi, M., Goli, N.E., Gholami, S. et al. QM and QM/MM study on inhibition mechanism of polyphenolic compounds as non-classical inhibitors of α-human carbonic anhydrase (II). Theor Chem Acc 140, 141 (2021). https://doi.org/10.1007/s00214-021-02839-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00214-021-02839-5

Keywords

Search

Navigation