Skip to main content

Advertisement

SpringerLink
Log in

Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study

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

Abstract

CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking–molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)—namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones.

3D structure of the Michaelis complex for Androstenedione-Aromatase

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
Fig. 15
Fig. 16
Fig. 17
Fig. 18

Similar content being viewed by others

References

  1. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD, Mendelson CR, Bulun SE (1994) Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 15:342–355

    CAS  Google Scholar 

  2. Brueggmeir RW, Hackett JC, Diaz-Cruz ES (2005) Aromatase inhibitors in the treatment of breast cancer. Endocr Rev 26:331–345

    Google Scholar 

  3. Plourde PV, Dyroff M, Dowsett M, Demers L, Yates R, Webster A (1995) Arimidex: a new oral, once-a-day aromatase inhibitor. J Steroid Biochem Mol Biol 53:175–179

    Google Scholar 

  4. Lipton A, Demers LM, Harvey HA, Kambic KB, Grossberg H, Brady C et al (1995) Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer 75:2132–2138

    Article  CAS  Google Scholar 

  5. Chen S, Zhang F, Sherman MA, Kijma I, Cho M, Yuan YC, Toma Y, Osawa Y, Zhou D, Eng ET (2003) Structure-function studies of aromatase and its inhibitors: a progress report. J Steroid Biochem Mol Biol 86:231–237

    Google Scholar 

  6. Gosh D, Griswold J, Erman M, Pangborn W (2009) Structural Basis for androgen specificity and estrogen synthesis in human aromatase. Nature 458:219–223

    Article  Google Scholar 

  7. Gosh D, Griswold J, Erman M, Pangborn W (2010) X-ray structure of human aromatase reveals an androgen-specific acive site. J Steroid Biochem Mol Biol 118:197–202

    Google Scholar 

  8. Hong Y, Li H, Yuan YC, Chen S (2009) Molecular characterization of aromatase. Ann NY Acad Sci 1155:112–120

    Google Scholar 

  9. Paoletta S, Stevenson GB, Wildeboer D, Eherman TM, Hylands PJ, Barlow DJ (2008) Screening of herbal constituents for aromatase inhibitory activity. Bioorg Med Chem 16:8466–8470

    Google Scholar 

  10. Takahashi M, Yamashita K, Numazawa M (2010) Probing the binding pocket of the active site of aromatase with 2-phenylaliphatic androsta-1,4-3,17-dione steroids. Steroids 75:330–337

    Article  CAS  Google Scholar 

  11. Cassidy CE, Setzer WN (2010) Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis. J Mol Model 16:311–326

    Google Scholar 

  12. Jackson T, Lawrence LW, Trusselle MN, Purhoit A, Reed MJ, Potter BVL (2008) Non-steroidal aromatase inhibitors based on a biphenyl scaffold: synthesis, in vitro SAR and molecular modeling. ChemMedChem 3:603–618

    Google Scholar 

  13. Chen S, Kao YC, Laughton CA (1997) Binding characteristics of aromatase inhibitors and phytoestrogens to human aromatase. J Steroid Biochem Mol Biol 61:107–115

    Google Scholar 

  14. Oliveira AA, Ramalho TC, da Cunha EFF (2009) QSAR study of androstenedione analogs as aromatase inhibitors. Lett Drug Des Discov 6:554–562

    Google Scholar 

  15. Favia AD, Cavalli A, Masetti M, Carotti A, Recanatini M (2006) Three dimensional model of the human aromatase enzyme and density functional parametrization of the iron containing protoporphyrin IX for a molecular dynamics study of heme-cysteinato cytochromes. Proteins 62:1074–1087

    Google Scholar 

  16. Graham-Lorence S, Amarneh B, White R.E, Peterson JA, Simpson ER (1995) A three dimensional model of aromatase cytochrome P450*. Protein Sci 4:1065–1080

    Google Scholar 

  17. Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovic D, Jhoti H (2003) Crystal structure of human cytochrome P450 2 C9 with bound warfarin. Nature 424:464–468

    Google Scholar 

  18. Roy PP, Roy K (2010) Docking and 3D-QSAR studies of diverse classes of human aromatase (CYP19) inhibitors. J Mol Model 16:1597–1616

    Google Scholar 

  19. Wood PM, Lawrence Woo LW, Labrosse JR, Trusselle MN, Abbate S, Longhi G, Castiglioni E, Lebon F, Purohit A, Reed MJ, Potter BVL (2008) Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity. J Med Chem 51:4226–4238

    Google Scholar 

  20. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 13:1605–1612

    Google Scholar 

  21. Onufriev A et al. (2011) H++ server homepage. http://biophysics.cs.vt.edu/

  22. Thomson EA, Siiteri PK (1974) Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J Biol Chem 249:5364–5372

    Google Scholar 

  23. O’Neal Johonston J (1998) Aromatase inhibitors. Crit Rev Biochem Mol Biol 33:375–405

    Google Scholar 

  24. Aktar M, Calder DL, Corina DL, Wright JN (1982) Mechanistic studies on C-19 demethylation in estrogen biosynthesis. Biochem J 201:569–580

    Google Scholar 

  25. Aktar M, Njar VC, Wright JN (1993) Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes. J Steroid Biochem Mol Biol 44:375–387

    Google Scholar 

  26. Silgar SG, Murray RI (1986) In: de Montellano PR Ortiz (ed) Cytochrome P-450: structure, mechanism and biochemistry, 3rd edn. Plenum, New York, p 429

  27. Poulos TL (1986) In: de Montellano PR Ortiz (ed) Cytochrome P-450: structure, mechanism and biochemistry, 3rd edn. Plenum, New York, p 505

  28. Waxman DJ (1986) In: de Montellano PR Ortiz (ed) Cytochrome P-450: structure, mechanism and biochemistry, 3rd edn. Plenum, New York, p 525

  29. Beunsen DD, Carrell HL, Covey DF (1987) Metabolism of 19-methyl-substituted steroids by human placental aromatase. Biochemistry 26:7833

    Google Scholar 

  30. Hackett JC, Brueggenmeier RW, Hadad CM (2005) The final catalytic step of cytochrome P450 aromatase: a density functional theory study. J Am Chem Soc 127:5244–5237

    Google Scholar 

  31. Still WC, Tempczyk A, Hawley RC, Hendrickson T (1990) Semianalytical treatment of solvation for molecular mechanics and dynamics. J Am Chem Soc 12:6127–6129

    Article  Google Scholar 

  32. Mohamadi F, Richards NGJ, Guida WC, Liskamp R, Lipton M, Caufied C, Chang G, Hendrickson T, Still WC (1990) Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics. J Comput Chem 11:440–467

    Article  CAS  Google Scholar 

  33. Weiner JS, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, Profeta S, Weiner PA Jr (1984) A new force field for molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 106:765–784

    Article  CAS  Google Scholar 

  34. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 162:785–791

    Google Scholar 

  35. Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145–1152

    Article  CAS  Google Scholar 

  36. Huey R, Goodsell DS, Morris GM, Olson AJ (2004) Grid-based hydrogen bond potentials with improved directionality. Lett Drug Des Discov 1:178–183

    Google Scholar 

  37. Oda A, Yamaotsu N, Hirono S (2005) New AMBER force field parameters of heme iron for cytochrome P450s determined by quantum chemical calculations of simplified models. J Comput Chem 26:818–826

    Google Scholar 

  38. Leimkuhler B, Skeel R (1994) Symplectic numerical integrators in constrained Hamiltonian systems. J Comput Phys 112:117–125

    Article  Google Scholar 

  39. Brunetti L, Galeazzi R, Orena M, Bottoni A (2008) Catalytic mechanism of L,L-diaminopimelic acid with diaminopimelate epimerase by molecular docking simulations. J Mol Graph Model 26:1082–1090

    Google Scholar 

  40. Melchiorre C, Andrisano V, Bolognesi ML, Budriesi R, Cavalli A, Cavrini V, Rosini M, Tumiatti V, Recanatini M (1998) Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer’s disease. J Med Chem 41:4186–4189

    Google Scholar 

  41. Rampa A, Bisi A, Valenti P, Recanatini M, Cavalli A, Andrisano V, Cavrini V, Fin L, Buriani A, Giust P (1998) Acetylcholinesterase inhibitors: synthesis and structure–activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)-methyl]aminoalkoxyheteroaryl derivatives. J Med Chem 41:3976–3986

    Google Scholar 

  42. Calvaresi M, Garavelli M, Bottoni A (2008) Computational evidence for catalytic mechanism of glutamine cyclase, a DFT investigation. Proteins 73:527–538

    Google Scholar 

  43. Stenta M, Calvaresi M, Altoè P, Spinelli D, Garavelli M, Galeazzi R, Bottoni A (2009) The catalytic mechanism of DAP epimerase: a QM/MM investigation. J Chem Theory Comput 5:1915–1930

    Google Scholar 

  44. Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens M, Castiglione-Geretsh M, Gelber RD, Rabaglio M, Smith I, Wardely A, Price KN, Goldhirsh A (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757

    Google Scholar 

  45. Jakesz R, Jonet W, Gnant M, Mittleboeck M, Grail R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H (2005) Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455–462

    Google Scholar 

  46. Furet P, Batzl C, Bathnagar A, Francotte E, Rihs G, Lang M (1993) Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds. J Med Chem 36:1393–1400

    Google Scholar 

  47. Jackson T, Lawrence Woo LW, Trusselle MN, Purohit A, Reed MJ, Potter BVL (2008) Non-steroidal aromatase inhibitors based on a biphenyl scaffold: synthesis, in vitro SAR and molecular modeling. ChemMedChem 3:603–618

    Google Scholar 

  48. Neves MAC, Dinis TCP, Colombo G, Sá e Melo ML (2009) Fast three dimensional pharmacophore virtual screening of new potent nonsteroid aromatase inhibitors. J Med Chem 52:143–150

  49. Cole PA, Robinson CH (1990) Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem 33:2933–2942

    Google Scholar 

  50. Hong Y, Cho M, Yuan YC, Chen S (2008) Molecular basis for the interaction of four different classes of substrates and inhibitors with human aromatase. Biochem Pharm 75:1161–1169

    Google Scholar 

  51. Lawrence Woo LW, Bubert C, Sutcliffe OB, Smith A, Chander SK, Mahon MF, Purohit A, Reed MJ, Potter BVL (2007) Dual aromatase–steroid sulfatase inhibitors. J Med Chem 50:3540–3560

    Google Scholar 

  52. Bikadi Z, Hazai E (2009) Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. J Chem Inf 1:15–31

    Google Scholar 

  53. Galeazzi R (2009) Molecular dynamics as a tool in rational drug design: current status and some major applications. Curr Comput Aided Drug Des 5:225–240

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento I.S.A.C, Università Politecnica delle Marche, via Brecce Bianche, 60131, Ancona, Italy

    Roberta Galeazzi & Luca Massaccesi

Authors
  1. Roberta Galeazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Massaccesi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberta Galeazzi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galeazzi, R., Massaccesi, L. Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study. J Mol Model 18, 1153–1166 (2012). https://doi.org/10.1007/s00894-011-1144-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-011-1144-y

Keywords

Search

Navigation