Skip to main content

Advertisement

SpringerLink
Log in

Quantum chemical study of silanediols as metal binding groups for metalloprotease inhibitors

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

DFT (B3LYP and M06L) as well as ab initio (MP2) methods with Dunning cc-pVnZ (n = 2,3) basis sets are employed for the study of the binding ability of the new class of protease inhibitors, i.e., silanediols, in comparison to the well-known and well-studied class of inhibitors with hydroxamic functionality (HAM). Active sites of metalloproteases are modeled by [R3M-OH2]2+ complexes, where R stands for ammonia or imidazole molecules and M is a divalent cation, namely zinc, iron or nickel (in their different spin states). The inhibiting activity is estimated by calculating Gibbs free energies of the water displacement by metal binding groups (MBGs) according to: [R3M-OH2]2+ + MBG → [R3M-MBG]2+ + H2O. The binding energy of silanediol is only a few kcal mol−1 inferior to that of HAM for zinc and iron complexes and is even slightly higher for the triplet state of the (NH3)3Ni2+ complex. For both MBGs studied in the ammonia model the binding ability is nearly the same, i.e., Fe2+(t) > Ni2+(t) > Fe2+(q) > Ni2+(s) > Zn2+. However, for the imidazole model the order is slightly different, i.e., Ni2+(t) > Fe2+(t) > Fe2+(q) > Ni2+(s) ≥ Zn2+. Equilibrium structures of the R3Zn 2+ complexes with both HAM and silanediol are characterized by the monodentate binding, but the bidentate character of binding increases on going to iron and nickel complexes. Two types of intermediates of the water displacement reactions for [(NH3)3M-OH2]2+ complexes were found which differ by the direction of the attack of the MBG. Hexacoordinated complexes exhibit bidentate bonding of MBGs and are lower in energy for M=Ni and Fe. For Zn penta- and hexacoordinated complexes have nearly the same energy. Intermediate complexes with imidazole ligands have only octahedral structures with bidentate bonding of both HAM and dimethylsilanediol molecules.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. Vallee BL, Auld DS (1993) Zinc: biological function and coordination motifs. Acc Chem Res 26:543–551

    Article  CAS  Google Scholar 

  2. Maret W, Li Y (2009) Coordination dynamics of zinc in proteins. Chem Rev 109:4682–4707

    Article  CAS  Google Scholar 

  3. Lipscomb WN, Sträter N (1996) Recent advances in zinc enzymology. Chem Rev 96:2375–2433

    Article  CAS  Google Scholar 

  4. Holm RH, Kennepohl P, Solomon EI (1996) Structural and functional aspects of metal sites in biology. Chem Rev 96:2239–2314

    Article  CAS  Google Scholar 

  5. Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401:188–193

    Article  CAS  Google Scholar 

  6. Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M, Renzoni D, Chakravarty P, Paolini C, De Francesco R, Gallinari P, Steinkuhler C, Di Marco S (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc Natl Acad Sci USA 101:15064–15069

    Article  CAS  Google Scholar 

  7. Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, Luong C, Arvai A, Buggy JJ, Chi E, Tang J, Sang BC, Verner E, Wynands R, Leahy EM, Dougan DR, Snell G, Navre M, Knuth MW, Swanson RV, McRee DE, Taric LW (2004) Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12:1325–1334

    Article  CAS  Google Scholar 

  8. Becker A, Schlichting I, Kabsch W, Groche D, Schultz S, Wagner AFV (1998) Iron center, substrate recognition, and mechanism of peptide deformylase. Nat Struct Biol 5:1053–1058

    Article  CAS  Google Scholar 

  9. Madison V, Duca J, Bennett F, Bohanon S, Cooper A, Chu M, Desai J, Girijavallabhan V, Hare R, Hruza A, Hendrata S, Huang Y, Kravec C, Malcolm B, McCormick J, Miesel L, Ramamanathan L, Reichert P, Saksena A, Wang J, Weber PC, Zhu H, Fischmann T (2002) Binding affinities and geometries of various metal ligands in peptide deformylase inhibitors. Biophys Chem 101–102:239–247

    Article  Google Scholar 

  10. Natesh R, Schwager SLU, Sturrock ED, Acharya KR (2003) Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature 421:551–554

    Article  CAS  Google Scholar 

  11. Christianson DW, Lipscomb WN (1989) Carboxypeptidase A. Acc Chem Res 22:62–69

    Article  CAS  Google Scholar 

  12. Mock WL, Zhang JZ (1991) Mechanistically significant diastereoselection in the sulfoximine inhibition of carboxypeptidase A. J Biol Chem 266:6393–6400

    CAS  Google Scholar 

  13. Fersht AR (1999) Enzyme structure and mechanism in protein science. Freeman, New York

    Google Scholar 

  14. Wu S, Zhang C, Xu D, Guo H (2010) Catalysis of carboxypeptidase A: promoted-water vs nucleophilic pathways. J Phys Chem B114:9259–9267

    Google Scholar 

  15. Gupta SP (2007) Quantitative structure-activity relationship studies on zinc-containing metalloproteinase inhibitors. Chem Rev 107:3042–3087

    Article  CAS  Google Scholar 

  16. Farkas E, Katz Y, Bhusare S, Reich R, Röschenthaler G-V, Königsmann M, Breuer E (2004) Carbamoylphosphonate Based Matrix Metalloproteinase (MMP) inhibitor metal complexes - solution studies and stability constants. Towards a zinc selective binding group. J Biol Inorg Chem 9:307–315

    Article  CAS  Google Scholar 

  17. Massie BM (1998) 15 years of heart-failure trials: what have we learned. Lancet 352(suppl I):SI29–33

    Article  Google Scholar 

  18. Burnier M, Brunner HR (2000) Angiotensin II receptor antagonists. Lancet 355:637–45

    Article  CAS  Google Scholar 

  19. Babine RE, Bender SL (1997) Molecular recognition of proteinminus signligand complexes: applications to drug design. Chem Rev 97:1359–1472

    Article  CAS  Google Scholar 

  20. Vane JR (1999) The history of inhibitors of angiotensin converting enzyme. J Physiol Pharmacol 50:489–498

    CAS  Google Scholar 

  21. Borkakoti N (2004) Matrix metalloprotease inhibitors: design from structure. Biochem Soc Trans 32:17–22

    Article  CAS  Google Scholar 

  22. Sieburth SM, Nittoli T, Mutahi AM, Guo L (1998) Silanediols-A new class of potent protease inhibitor. Angew Chem Int Ed 37:812–814

    Article  CAS  Google Scholar 

  23. Chen CA, Sieburth SM, Glekas A, Hewitt GW, Trainor GL, Erickson-Viitanen S, Garber SS, Cordova B, Jeffry S, Klabe RM (2001) Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease. Chem Biol 8:1161–1166

    Article  CAS  Google Scholar 

  24. Mutahi MW, Nittoli T, Guo L, Sieburth SM (2002) Silicon-based metalloprotease inhibitors: synthesis and evaluation of silanol and silanediol peptide analogues as inhibitors of angiotensin-converting enzyme. J Am Chem Soc 124:7363–7375

    Article  CAS  Google Scholar 

  25. Kim J, Glekas A, Sieburth SM (2002) Silanediol-based inhibitor of thermolysin. Bioorg Med Chem Lett 12:3625

    Article  CAS  Google Scholar 

  26. Juers DH, Kim J, Matthews BW, Sieburth SM (2005) Structural analysis of silanediols as transition-state-analogue inhibitors of the benchmark metalloprotease thermolysin. Biochem 44:16524–16528

    Article  CAS  Google Scholar 

  27. El Yazal J, Pang YP (1999) Novel stable configurations and tautomers of the neutral and deprotonated hydroxamic acids predicted from high-level Ab initio calculations. J Phys Chem A 103:8346–8350

    Article  CAS  Google Scholar 

  28. El Yazal J, Pang YP (1999) Ab initio calculations of proton dissociation energies of zinc ligands: hypothesis of imidazolate as zinc ligand in proteins. J Phys Chem B 103:8773–8779

    Article  CAS  Google Scholar 

  29. El Yazal J, Pang YP (2000) Proton dissociation energies of zinc-coordinated hydroxamic acids and their relative affinities for zinc: insight into design of inhibitors of zinc- containing proteinases. J Phys Chem B 104:6499–6504

    Article  CAS  Google Scholar 

  30. Deerfield DW, Carter C, Pedersen LG (2001) Models for protein–zinc ion binding sites II. The catalytic sites. Int J Quant Chem 83:150–165

    Article  CAS  Google Scholar 

  31. Remko M, Garaj V (2003) Thermodynamics of binding of Zn2+ to carbonic anhydrase inhibitors. Mol Phys 101:2357–2368

    Article  CAS  Google Scholar 

  32. Cheng F, Zhang R, Luo X, Shen J, Li X, Gu J, Zhu W, Shen J, Sagi I, Ji R, Chen K, Jiang H (2002) Quantum chemistry study on the interaction of the exogenous ligands and the catalytic zinc ion in matrix metalloproteinases. J Phys Chem B 106:4552–4559

    Article  CAS  Google Scholar 

  33. Khandelwal A, Lukacova V, Comez D, Kroll DM, Raha S, Balaz S (2005) A combination of docking, QM/MM, and MD simulation for binding affinity estimation of metalloprotein ligands. J Med Chem 48:5437–5447

    Article  CAS  Google Scholar 

  34. Linder DP, Rodgers KR (2004) Theoretical study of imidazole- and thiol-based zinc binding groups relevant to inhibition of metzincins. J Phys Chem B 108:13839–13849

    Article  CAS  Google Scholar 

  35. Šramko M, Garaj V, Remko M (2008) Thermodynamics of binding of angiotensin-converting enzyme inhibitors to enzyme active site model. J Mol Struct (THEOCHEM) 869:19–28

    Article  Google Scholar 

  36. Dobbs KD, Rinehart AM, Howard MH, Zheng YJ, Kleier DA (2006) Computational characterization of metal binding groups for metalloenzyme inhibitors. J Chem Theor Comput 2:990–996

    Article  CAS  Google Scholar 

  37. Vanommeslaeghe K, Loverix S, Geerlings P, Tourwé D (2005) DFT-based ranking of zinc-binding groups in histone deacetylase inhibitors. Bioorg Med Chem 13:6070–6082

    Article  CAS  Google Scholar 

  38. Vanommeslaeghe K, Van Alsenoy C, De Proft F, Martins JC, Tourwé D, Geerlings P (2003) Ab initio study of the binding of Trichostatin A (TSA) in the active site of histone deacetylase like protein (HDLP). Org Biomol Chem 1:2951–2957

    Article  CAS  Google Scholar 

  39. Vanommeslaeghe K, De Proft F, Loverix S, Tourwé D, Geerlings P (2005) Theoretical study revealing the functioning of a novel combination of catalytic motifs in histone deacetylase. Bioorg Med Chem 13:3987–3992

    Article  CAS  Google Scholar 

  40. Corminboef C, Hu P, Tuckerman ME, Zhang Y (2006) Unexpected deacetylation mechanism suggested by a density functional theory QM/MM study of histone-deacetylase-like protein. J Am Chem Soc 128:4530–4531

    Article  Google Scholar 

  41. Frison G, Ohanessian G (2008) A comparative study of semiempirical, ab initio, and DFT methods in evaluating metal-ligand bond strength, proton affinity, and interactions between first and second shell ligands in Zn-biomimetic complexes. J Comput Chem 29:416–433

    Article  CAS  Google Scholar 

  42. Elstner M, Cui Q, Munih P, Kaxiras E, Frauenheim T, Karplus M (2003) Modeling Zinc in biomolecules with the self consistent charge-density functional tight binding (SCC-DFTB) method: Applications to structural and energetic analysis. J Comput Chem 24:565–581

    Article  CAS  Google Scholar 

  43. Marmion CJ, Griffith D, Nolan KB (2004) Hydroxamic acids - an intriguing family of bioligands and enzyme inhibitors. Eur J Inorg Chem 15:3003–3016

    Article  Google Scholar 

  44. Codd R (2008) Traversing the coordination chemistry and chemical biology of hydroxamic acids. Coord Chem Rev 252:1387–1408

    Article  CAS  Google Scholar 

  45. Wang D, Helquist P, Wiest O (2007) Zinc binding in HDAC inhibitors: a DFT study. J Org Chem 72:5446–5449

    Article  CAS  Google Scholar 

  46. Wu R, Lu Z, Cao Z, Zhang Y (2011) Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel. J Am Chem Soc 133:6110–6113

    Article  CAS  Google Scholar 

  47. Becke AD (1993) Density-functional thermochemistry III. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  48. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti conelation energy formula into a functional of the electron density. Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  49. Zhao Y, Truhlar DG (2006) A new local density functional for main-group thermochemistry, transition metal bonding, thermochemical kinetics, and noncovalent interactions. J Chem Phys 125:194101

    Article  Google Scholar 

  50. Zhao Y, Truhlar DG (2008) 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 120:215–241

    Article  CAS  Google Scholar 

  51. Amin EA, Truhlar DG (2008) Zn coordination chemistry: development of benchmark suites for geometries, dipole moments, and bond dissociation energies and their use to test and validate density functionals and molecular orbital theory. J Chem Theor Comput 4:75–85

    Article  CAS  Google Scholar 

  52. Sorkin A, Iron MA, Truhlar DG (2008) Density functional theory in transition-metal chemistry: relative energies of low-lying states of iron compounds and the effect of spatial symmetry breaking. J Chem Theor Comput 4:307–315

    Article  CAS  Google Scholar 

  53. Cramer CJ, Truhlar DG (2009) Density functional theory for transition metals and transition metal chemistry. Phys Chem Chem Phys 11:10757–10816

    Article  CAS  Google Scholar 

  54. Zeng Y, Wang S, Feng H, Xie Y, King RB (2011) Highly unsaturated binuclear butadiene iron carbonyls: quintet spin States, perpendicular structures, agostic hydrogen atoms, and iron-iron multiple bonds. Int J Mol Sci 12:2216–2231

    Article  CAS  Google Scholar 

  55. Binkley JS, Pople JA (1975) Møller–Plesset theory for atomic ground state energies. Int J Quant Chem 9:229–236

    Article  CAS  Google Scholar 

  56. 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 132:154104

    Article  Google Scholar 

  57. Woon DE, Dunning TH (1993) Gaussian basis sets for use in correlated molecular calculations. III. The atoms aluminum through argon. J Chem Phys 98:1358–1371

    Article  CAS  Google Scholar 

  58. Frisch MJ et al. (2009) Gaussian 09, Revision B.01. Gaussian, Wallingford

  59. Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem Rev 88:899–926

    Article  CAS  Google Scholar 

  60. Glendening ED, Reed AE, Carpenter JE, Weinhold F (1988) NBO v3.1, Madison

  61. Akesson R, Pettersson LGM, Sandstrom M, Siegbahn PEM, Wahlgrent U (1993) Theoretical study of water-exchange reactions for the divalent ions of the first transition period. J Phys Chem 97:3765–3774

    Article  CAS  Google Scholar 

  62. Dudev T, Lim C (2003) Principles governing Mg, Ca, and Zn binding and selectivity in proteins. Chem Rev 103:773–788

    Article  CAS  Google Scholar 

  63. He H, Puerta DT, Cohen SM, Rodgers KR (2005) Spectroscopic study of reactions between chelating zinc-binding groups and mimics of the MMP and ADAM catalytic sites: the coordination chemistry of metalloprotease inhibition. Inorg Chem 44:7431–7442

    Article  CAS  Google Scholar 

  64. Bertrand P (2010) Inside HDAC with HDAC inhibitors. Eur J Med Chem 45:2095–2116

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physical and Analytical Chemistry. Experimental Sciences Faculty, University of Jaén, Campus “Las Lagunillas”, 23071, Jaen, Spain

    Manuel Montejo, Pilar Gema Rodríguez Ortega & Juan Jesús López González

  2. Department of Chemistry, Radiochemistry Laboratory, St. Petersburg State University, St. Petersburg, 199034, Russia

    Igor S. Ignatyev

Authors
  1. Igor S. Ignatyev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuel Montejo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pilar Gema Rodríguez Ortega
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juan Jesús López González
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan Jesús López González.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ignatyev, I.S., Montejo, M., Rodríguez Ortega, P.G. et al. Quantum chemical study of silanediols as metal binding groups for metalloprotease inhibitors. J Mol Model 19, 1819–1834 (2013). https://doi.org/10.1007/s00894-012-1745-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-012-1745-0

Keywords

Search

Navigation