Effect of donor atom identity on metal-binding pharmacophore coordination

  • Benjamin L. Dick
  • Ashay Patel
  • J. Andrew McCammon
  • Seth M. Cohen
Original Paper

Abstract

The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms influences the response of the ligand to changes in the protein active site environment. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.

Keywords

Computational chemistry Density functional theory Ligand binding Metalloenzyme X-ray crystallography 

Supplementary material

775_2017_1454_MOESM1_ESM.pdf (1.7 mb)
Supplementary material 1 (PDF 1722 kb)

References

  1. 1.
    Andreini C, Bertini I, Cavallaro G, Holliday GL, Thornton JM (2008) J Biol Inorg Chem 13:1205–1218CrossRefPubMedGoogle Scholar
  2. 2.
    Rouffet M, Cohen SM (2011) Dalton Trans 40:3445–3454CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Supuran CT, Scozzafava A, Casini A (2003) Med Res Rev 23:146–189CrossRefPubMedGoogle Scholar
  4. 4.
    Paris M, Porcelloni M, Binaschi M, Fattori D (2008) J Med Chem 51:1505–1529CrossRefPubMedGoogle Scholar
  5. 5.
    Fernández-Montero JV, Vispo E, Soriano V (2014) Expert Opin Pharmacother 15:211–219CrossRefPubMedGoogle Scholar
  6. 6.
    Jacobsen FE, Lewis JA, Cohen SM (2007) ChemMedChem 2:152–171CrossRefPubMedGoogle Scholar
  7. 7.
    Mutule I, Borovika D, Rozenberga E, Romanchikova N, Zalubovskis R, Shestakova I, Trapencieris P (2015) J Enzyme Inhib Med Chem 30:216–223CrossRefPubMedGoogle Scholar
  8. 8.
    Puerta DT, Lewis JA, Cohen SM (2004) J Am Chem Soc 126:8388–8389CrossRefPubMedGoogle Scholar
  9. 9.
    Göçer H, Akincioğlu A, Göksu S, Gülçin İ, Supuran CT (2015) J Enzyme Inhib Med Chem 30:316–320CrossRefPubMedGoogle Scholar
  10. 10.
    Moradei O, Vaisburg A, Martell RE (2008) Curr Top Med Chem 8:841–858CrossRefPubMedGoogle Scholar
  11. 11.
    Martin DP, Hann ZS, Cohen SM (2013) Inorg Chem 52:12207–12215CrossRefPubMedGoogle Scholar
  12. 12.
    Martin DP, Blachly PG, Marts AR, Woodruff TM, de Oliveira CAF, McCammon JA, Tierney DL, Cohen SM (2014) J Am Chem Soc 136:5400–5406CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Puerta DT, Cohen SM (2003) Inorg Chem 42:3423–3430CrossRefPubMedGoogle Scholar
  14. 14.
    Puerta DT, Schames JR, Henchman RH, McCammon JA, Cohen SM (2003) Angew Chem Int Ed Engl 42:3772–3774CrossRefPubMedGoogle Scholar
  15. 15.
    Cook SA, Hill EA, Borovik AS (2015) Biochemistry 54:4167–4180CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Jacobsen FE, Lewis JA, Heroux KJ, Cohen SM (2007) Inorg Chim Acta 360:264–272CrossRefGoogle Scholar
  17. 17.
    Nair SK, Krebs JF, Christianson DW, Fierke CA (1995) Biochemistry 34:3981–3989CrossRefPubMedGoogle Scholar
  18. 18.
    Machiguchi T, Hasegawa T, Kano Y (1993) Bull Chem Soc Jpn 66:3699–3706CrossRefGoogle Scholar
  19. 19.
    Monnard FW, Heinisch T, Nogueira ES, Schirmer T, Ward TR (2011) Chem Commun (Camb) 47:8238–8240CrossRefGoogle Scholar
  20. 20.
    Yung-Chi C, Prusoff WH (1973) Biochem Pharmacol 22:3099–3108CrossRefGoogle Scholar
  21. 21.
    Avvaru BS, Kim CU, Sippel KH, Gruner SM, Agbandje-McKenna M, Silverman DN, McKenna R (2010) Biochemistry 49:249–251CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Murshudov GN, Vagin AA, Dodson EJ (1997) Acta Crystallogr Sect D: Biol Crystallogr 53:240–255CrossRefGoogle Scholar
  23. 23.
    Emsley P, Cowtan K (2004) Acta Crystallogr Sect D: Biol Crystallogr 60:2126–2132CrossRefGoogle Scholar
  24. 24.
    Schüttelkopf AW, van Aalten DMF (2004) Acta Crystallogr Sect D: Biol Crystallogr 60:1355–1363CrossRefGoogle Scholar
  25. 25.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd J, Brothers EN, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09. Gaussian Inc., WallingfordGoogle Scholar
  26. 26.
    Becke AD (1993) J Chem Phys 98:5648CrossRefGoogle Scholar
  27. 27.
    Lee C, Yang W, Parr RG (1988) Phys Rev B 37:785–789CrossRefGoogle Scholar
  28. 28.
    Stephens PJ, Devlin FJ, Chabalowski CF, Frisch MJ (1994) J Phys Chem 98:11623–11627CrossRefGoogle Scholar
  29. 29.
    Vosko SH, Wilk L, Nusair M (1980) Can J Phys 58:1200–1211CrossRefGoogle Scholar
  30. 30.
    Barone V, Cossi M (1998) J Phys Chem A 102:1995–2001CrossRefGoogle Scholar
  31. 31.
    Cossi M, Rega N, Scalmani G, Barone V (2003) J Comput Chem 24:669–681CrossRefPubMedGoogle Scholar
  32. 32.
    Klamt A, Schüürmann G (1993) J. Chem. Soc. Perkin Trans. 2:799–805CrossRefGoogle Scholar
  33. 33.
    Ryde U (1999) Biophys J 77:2777–2787CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Dudev T, Lim C (2000) J Am Chem Soc 122:11146–11153CrossRefGoogle Scholar
  35. 35.
    Jacobsen JA, Fullagar JL, Miller MT, Cohen SM (2011) J Med Chem 54:591–602CrossRefPubMedGoogle Scholar
  36. 36.
    Costa G, Gidaro MC, Vullo D, Supuran CT, Alcaro S (2016) J Agric Food Chem 64:5295–5300CrossRefPubMedGoogle Scholar
  37. 37.
    Schulze Wischeler J, Innocenti A, Vullo D, Agrawal A, Cohen SM, Heine A, Supuran CT, Klebe G (2010) ChemMedChem 5:1609–1615CrossRefPubMedGoogle Scholar
  38. 38.
    Martin DP, Blachly PG, McCammon JA, Cohen SM (2014) J Med Chem 57:7126–7135CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Sigel H, McCormick DB (1970) Acc Chem Res 3:201–208CrossRefGoogle Scholar

Copyright information

© SBIC 2017

Authors and Affiliations

  • Benjamin L. Dick
    • 1
  • Ashay Patel
    • 1
  • J. Andrew McCammon
    • 1
    • 2
    • 3
    • 4
  • Seth M. Cohen
    • 1
  1. 1.Department of Chemistry and BiochemistryUniversity of California San DiegoLa JollaUSA
  2. 2.Department of PharmacologyUniversity of California San DiegoLa JollaUSA
  3. 3.Howard Hughes Medical InstituteUniversity of California San DiegoLa JollaUSA
  4. 4.National Biomedical Computation ResourceUniversity of California San DiegoLa JollaUSA

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