Advertisement

Structural Chemistry

, Volume 30, Issue 5, pp 1779–1793 | Cite as

Mechanistic insights into the inhibition mechanism of cysteine cathepsins by chalcone-based inhibitors—a QM cluster model approach

  • C. Pitchumani Violet Mary
  • R. Shankar
  • S. VijayakumarEmail author
Original Research
  • 52 Downloads

Abstract

Cathepsins are the most abundant cysteine proteases involved in many physiological processes. The imbalance between the natural cysteine protease inhibitors and cathepsins leads to many pathological conditions such as cancer, osteoporosis, and osteoarthritis. Thus, cysteine cathepsins have turn out to be an attractive therapeutic target for the development of new inhibitors. In this paper, the computational study of the inhibition mechanism of cysteine protease by chalcone-based inhibitors has been carried out by means of quantum chemical calculations by employing DFT method. The present study exposes how the processes of activation of the reactive centers of the chalcone derivatives and the nucleophilic attack by the cysteine residue at the electrophilic reactive site of the chalcone take place in the catalytic active site. The obtained results reveal that the inhibition reaction proceeds in a stepwise manner and the attack of the cysteine residue will be either at carbonyl carbon C32 (pathway 1) or β-carbon C33 (pathway 2). The low positive activation (5.61 and 4.58 kcal/mol) and reaction (1.60 and 9.70 kcal/mol) energies corresponding to both the pathways along with the positive ∇2ρ(r) values for C32/33–S6 bonds imply that the overall reaction is endothermic and the nature of inhibitor is reversible covalent.

Keywords

Cysteine protease Catalytic dyad Inhibition mechanism QM cluster DFT Chalcone 

Notes

Acknowledgements

The authors (C. Pitchumani Violet Mary and S.Vijayakumar) thank the Department of Science and Technology–Science and Engineering Research Board (DST-SERB), India, for awarding this research project under the OYS Scheme (Grant. No. SR/FTP/PS-115/2011 dated 19/09/2013).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11224_2018_1273_MOESM1_ESM.docx (105 kb)
ESM 1 (DOCX 105 kb)

References

  1. 1.
    Turk B, Turk D, Turk V (2000) Lysosomal cysteine proteases: more than scavengers. Biochim Biophys Acta - Protein Struct Mol Enzymol 1477:98–111.  https://doi.org/10.1016/S0167-4838(99)00263-0 CrossRefGoogle Scholar
  2. 2.
    Berti PJ, Storer AC (1995) Alignment/phylogeny of the papain superfamily of cysteine proteases. J Mol Biol 246:273–283.  https://doi.org/10.1006/jmbi.1994.0083 CrossRefGoogle Scholar
  3. 3.
    Vasiljeva O, Reinheckel T, Peters C et al (2007) Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des 13:387–403.  https://doi.org/10.2174/138161207780162962 CrossRefGoogle Scholar
  4. 4.
    Chapman HA, Riese RJ, Shi GP (1997) Emerging roles for cysteine proteases in human biology. Annu Rev Physiol 59:63–88.  https://doi.org/10.1146/annurev.physiol.59.1.63 CrossRefGoogle Scholar
  5. 5.
    Turk V, Bode W (1991) The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett 285:213–219.  https://doi.org/10.1016/0014-5793(91)80804-C CrossRefGoogle Scholar
  6. 6.
    Josiah O, Chaudhuri G (2010) Cystatin superfamily. J Heal Care Poor Underserved 21:51–70.  https://doi.org/10.1353/hpu.0.0257 CrossRefGoogle Scholar
  7. 7.
    Abrahamson M, Barrett AJ, Salvesen G, Grubb A (1986) Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J Biol Chem 261:11282–11289Google Scholar
  8. 8.
    Lutgens SPM, Cleutjens KBJM, Daemen MJAP, Heeneman S (2007) Cathepsin cysteine proteases in cardiovascular disease. FASEB J 21:3029–3041.  https://doi.org/10.1096/fj.06-7924com CrossRefGoogle Scholar
  9. 9.
    Salgado JV, Souza FL, Salgado BJ (2013) How to understand the association between cystatin C levels and cardiovascular disease: imbalance, counterbalance, or consequence? J Cardiol 62:331–335.  https://doi.org/10.1016/j.jjcc.2013.05.015 CrossRefGoogle Scholar
  10. 10.
    Bökenkamp A, Herget-Rosenthal S, Bökenkamp R (2006) Cystatin C, kidney function and cardiovascular disease. Pediatr Nephrol 21:1223–1230.  https://doi.org/10.1007/s00467-006-0192-5 CrossRefGoogle Scholar
  11. 11.
    Lafarge JC, Naour N, Clément K, Guerre-Millo M (2010) Cathepsins and cystatin C in atherosclerosis and obesity. Biochimie 92:1580–1586.  https://doi.org/10.1016/j.biochi.2010.04.011 CrossRefGoogle Scholar
  12. 12.
    Mottram JC, Brooks DR, Coombs GH (1998) Roles of cysteine proteinases of trypanosomes and Leishmania in host-parasite interactions. Curr Opin Microbiol 1:455–460.  https://doi.org/10.1016/S1369-5274(98)80065-9 CrossRefGoogle Scholar
  13. 13.
    Sajid M, McKerrow JH (2002) Cysteine proteases of parasitic organisms. Mol Biochem Parasitol 120:1–21.  https://doi.org/10.1016/S0166-6851(01)00438-8CrossRefGoogle Scholar
  14. 14.
    Rosenthal PJ (2004) Cysteine proteases of malaria parasites. Int J Parasitol 34:1489–1499.  https://doi.org/10.1016/j.ijpara.2004.10.003 CrossRefGoogle Scholar
  15. 15.
    Rosenthal P, Sijwali P, Singh A, Shenai B (2002) Cysteine proteases of malaria parasites: targets for chemotherapy. Curr Pharm Des 8:1659–1672.  https://doi.org/10.2174/1381612023394197 CrossRefGoogle Scholar
  16. 16.
    Turk D, Gunčar G (2003) Lysosomal cysteine proteases (cathepsins): promising drug targets. Acta Crystallogr Sect D: Biol Crystallogr 59:203–213.  https://doi.org/10.1107/S0907444902021479 CrossRefGoogle Scholar
  17. 17.
    Storer AC, Menard R (1994) Catalytic mechanism in papain family of cysteine peptidases. Methods Enzymol 244:486–500.  https://doi.org/10.1016/0076-6879(94)44035-2 CrossRefGoogle Scholar
  18. 18.
    Tian BX, Eriksson LA (2011) Catalytic mechanism and roles of Arg197 and Thr183 in the staphylococcus aureus sortase A enzyme. J Phys Chem B 115:13003–13011.  https://doi.org/10.1021/jp2058113 CrossRefGoogle Scholar
  19. 19.
    Mladenovic M, Fink RF, Thiel W et al (2008) On the origin of the stabilization of the zwitterionic resting state of cysteine proteases: a theoretical study. J Am Chem Soc 130:8696–8705.  https://doi.org/10.1021/ja711043x CrossRefGoogle Scholar
  20. 20.
    Schwöbel JAH, Wondrousch D, Koleva YK et al (2010) Prediction of Michael-type acceptor reactivity toward glutathione. Chem Res Toxicol 23:1576–1585.  https://doi.org/10.1021/tx100172x CrossRefGoogle Scholar
  21. 21.
    Otto H-H, Schirmeister T (1997) Cysteine proteases and their inhibitors. Chem Rev 97:133–172.  https://doi.org/10.1021/cr950025u CrossRefGoogle Scholar
  22. 22.
    Lounnas V, Ritschel T, Kelder J et al (2013) Current progress in structure-based rational drug design marks a new mindset in drug discovery. Comput Struct Biotechnol J 5:e201302011.  https://doi.org/10.5936/csbj.201302011 CrossRefGoogle Scholar
  23. 23.
    Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 3:935–949.  https://doi.org/10.1038/nrd1549 CrossRefGoogle Scholar
  24. 24.
    Lavecchia A, Giovanni C (2013) Virtual screening strategies in drug discovery: a critical review. Curr Med Chem 20:2839–2860.  https://doi.org/10.2174/09298673113209990001 CrossRefGoogle Scholar
  25. 25.
    Sliwoski G, Kothiwale S, Meiler J, Lowe Jr EW (2014) Computational methods in drug discovery. Pharmacol Rev 66:334–395CrossRefGoogle Scholar
  26. 26.
    Himo F (2017) Recent trends in quantum chemical modeling of enzymatic reactions. J Am Chem Soc 139:6780–6786.  https://doi.org/10.1021/jacs.7b02671 CrossRefGoogle Scholar
  27. 27.
    Náray-Szabó G, Oláh J, Krámos B (2013) Quantum mechanical modeling: a tool for the understanding of enzyme reactions. Biomolecules 3:662–702.  https://doi.org/10.3390/biom3030662 CrossRefGoogle Scholar
  28. 28.
    Siegbahn PEM, Himo F (2011) The quantum chemical cluster approach for modeling enzyme reactions. Wiley Interdiscip Rev: Comput Mol Sci 1:323–336.  https://doi.org/10.1002/wcms.13 Google Scholar
  29. 29.
    Shankar R, Kolandaivel P (2007) Reaction mechanism of O-acylhydroxamate with cysteine proteases. J Chem Sci 119:533–544.  https://doi.org/10.1007/s12039-007-0067-8 CrossRefGoogle Scholar
  30. 30.
    Shankar R, Kolandaivel P, Senthilkumar K (2010) Reaction mechanism of cysteine proteases model compound HSH with diketone inhibitor PhCOCOCH3-nXn, (X = F, Cl, n = 0, 1, 2). Int J Quantum Chem 110:1660–1674.  https://doi.org/10.1002/qua.22332 Google Scholar
  31. 31.
    Vijayakumar S, Kolandaivel P (2008) Reaction mechanism of HSH and CH3SH with NH2CH2COCH2X (X = F and Cl) molecules. Int J Quantum Chem 108:927–936.  https://doi.org/10.1002/qua.21555 CrossRefGoogle Scholar
  32. 32.
    Méndez-Lucio O, Romo-Mancillas A, Medina-Franco JL, Castillo R (2012) Computational study on the inhibition mechanism of cruzain by nitrile-containing molecules. J Mol Graph Model 35:28–35.  https://doi.org/10.1016/j.jmgm.2012.01.003 CrossRefGoogle Scholar
  33. 33.
    Mladenovic M, Ansorg K, Fink RF et al (2008) Atomistic insights into the inhibition of cysteine proteases: first QM/MM calculations clarifying the stereoselectivity of epoxide-based inhibitors. J Phys Chem B 112:11798–11808.  https://doi.org/10.1021/jp803895f CrossRefGoogle Scholar
  34. 34.
    Grazioso G, Legnani L, Toma L et al (2012) Mechanism of falcipain-2 inhibition by α,β-unsaturated benzo[1,4]diazepin-2-one methyl ester. J Comput Aided Mol Des 26:1035–1043.  https://doi.org/10.1007/s10822-012-9596-4 CrossRefGoogle Scholar
  35. 35.
    Quesne MG, R a W, de Visser SP (2013) Cysteine protease inhibition by nitrile-based inhibitors: a computational study. Front Chem 1:1–10.  https://doi.org/10.3389/fchem.2013.00039 CrossRefGoogle Scholar
  36. 36.
    Iqbal J, Abbasi BA, Mahmood T et al (2017) Plant-derived anticancer agents: a green anticancer approach. Asian Pac J Trop Biomed 7:1129–1150.  https://doi.org/10.1016/j.apjtb.2017.10.016 CrossRefGoogle Scholar
  37. 37.
    Wang H, Oo Khor T, Shu L et al (2012) Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability. Anti Cancer Agents Med Chem 12:1281–1305.  https://doi.org/10.2174/187152012803833026 CrossRefGoogle Scholar
  38. 38.
    Singh S, Sharma B, Kanwar SS, Kumar A (2016) Lead phytochemicals for anticancer drug development. Front Plant Sci 7:1–13.  https://doi.org/10.3389/fpls.2016.01667 Google Scholar
  39. 39.
    Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3:768–780.  https://doi.org/10.1038/nrc1189 CrossRefGoogle Scholar
  40. 40.
    Singh P, Anand A, Kumar V (2014) Recent developments in biological activities of chalcones: a mini review. Eur J Med Chem 85:758–777.  https://doi.org/10.1016/j.ejmech.2014.08.033 CrossRefGoogle Scholar
  41. 41.
    Srinivasan B, Johnson TE, Lad R, Xing C (2009) Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3′,4′,5′-tetramethoxychalcone and its analogues as potent nuclear factor κB inhibitors and their anticancer activities. J Med Chem 52:7228–7235.  https://doi.org/10.1021/jm901278z CrossRefGoogle Scholar
  42. 42.
    Dinkova-Kostova AT, Abeygunawardana C, Talalay P (1998) Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers. J Med Chem 41:5287–5296.  https://doi.org/10.1021/jm980424s CrossRefGoogle Scholar
  43. 43.
    Gan F-F, Kaminska KK, Yang H et al (2013) Identification of Michael acceptor-centric pharmacophores with substituents that yield strong thioredoxin reductase inhibitory character correlated to antiproliferative activity. Antioxid Redox Signal 19:1149–1165.  https://doi.org/10.1089/ars.2012.4909 CrossRefGoogle Scholar
  44. 44.
    Dinkova-Kostova AT, Massiah MA, Bozak RE et al (2001) Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci U S A 98:3404–3409.  https://doi.org/10.1073/pnas.051632198 CrossRefGoogle Scholar
  45. 45.
    Ravish I, Raghav N (2015) SAR studies of differently functionalized 4′-phenylchalcone based compounds as inhibitors of cathepsins B, H and L. RSC Adv 5:50440–50453.  https://doi.org/10.1039/C5RA00357A CrossRefGoogle Scholar
  46. 46.
    Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789.  https://doi.org/10.1103/PhysRevB.37.785 CrossRefGoogle Scholar
  47. 47.
    Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Phys Rev A 38:3098–3100.  https://doi.org/10.1103/PhysRevA.38.3098 CrossRefGoogle Scholar
  48. 48.
    Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648-5652.  https://doi.org/10.1063/1.464913 CrossRefGoogle Scholar
  49. 49.
    Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3094.  https://doi.org/10.1021/cr9904009 CrossRefGoogle Scholar
  50. 50.
    Tomasi J, Mennucci B, Cancès E (1999) The IEF version of the PCM solvation method: an overview of a new method addressed to study molecular solutes at the QM ab initio level. J Mol Struct THEOCHEM 464:211–226.  https://doi.org/10.1016/S0166-1280(98)00553-3 CrossRefGoogle Scholar
  51. 51.
    Da CJ, Head-Gordon M (2008) Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections. Phys Chem Chem Phys 10:6615–6620.  https://doi.org/10.1039/b810189b CrossRefGoogle Scholar
  52. 52.
    Burns LA, Vázquez-Mayagoitia Á, Sumpter BG, Sherrill CD (2011) Density-functional approaches to noncovalent interactions: a comparison of dispersion corrections (DFT-D), exchange-hole dipole moment (XDM) theory, and specialized functionals. J Chem Phys 134:084107.  https://doi.org/10.1063/1.3545971 CrossRefGoogle Scholar
  53. 53.
    Popelier PLA (1998) MORPHY98 a program written by PLA Popelier with a contribution from RGA Bone. UMIST, ManchesterGoogle Scholar
  54. 54.
    Domingo LR, Ríos-Gutiérrez M, Pérez P (2016) Applications of the conceptual density functional theory indices to organic chemistry reactivity. Molecules 21.  https://doi.org/10.3390/molecules21060748
  55. 55.
    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, Peralta Jr JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi Pomelli RC, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.1. Gaussian, Inc, WallingfordGoogle Scholar
  56. 56.
    Karelson M, Lobanov VS, Katritzky AR (1996) Quantum-chemical descriptors in QSAR/QSPR studies. Chem Rev 96:1027–1044.  https://doi.org/10.1021/cr950202r CrossRefGoogle Scholar
  57. 57.
    Domingo LR, Aurell MJ, Perez P et al (2002) Quantitative characterization of the global electrophilicity power of common diene/dienophile pairs in Diels-Alder reactions. Tetrahedron 58:4417–4423.  https://doi.org/10.1016/S0040-4020(02)00410-6 CrossRefGoogle Scholar
  58. 58.
    Zhuang C, Zhang W, Sheng C et al (2017) Chalcone: a privileged structure in medicinal chemistry. Chem Rev 117:7762–7810.  https://doi.org/10.1021/acs.chemrev.7b00020 CrossRefGoogle Scholar
  59. 59.
    Janiak C (2000) A critical account on π-π stacking in metal complexes with aromatic nitrogen-containing ligands. J Chem Soc Dalton Trans 3885–3896.  https://doi.org/10.1039/b003010o

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PhysicsBharathiar UniversityCoimbatoreIndia
  2. 2.Department of Medical PhysicsBharathiar UniversityCoimbatoreIndia

Personalised recommendations