Cathepsin B is one of the attractive targets for cancer treatments due to its prominent role in tumor cell invasion and metastasis. Because of the increasing toxicity of available cancer drugs, it is essential to develop new drugs with less or no side effects. One of the natural compounds named curcumin has a well-documented history of medicine in India, which is currently in clinical trials for the treatment of various cancers. However, the inhibition mechanism of the curcumin molecule is not yet clear. In this present study, the inhibition of cathepsin B by the curcumin has been studied by quantum chemical methods using DFT method at M062X/6-31 + g(d,p)//B3LYP/6-31g(d) level of theory to obtain a complete picture of possible reaction paths. Based on the obtained results, the Cys29 can undergo nucleophilic attack at any one of the four reactive sites of the curcumin. The low activation energy 1.43 kcal/mol along with low negative reaction energy − 6.82 kcal/mol suggests that attack of Cys29 at C63 atom is the most feasible reaction path. These results suggest that curcumin can be used to develop less toxic cathepsin B inhibitors for the treatment of cancer disease.
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Quantum theory of atoms in molecules
Siegel RL, Miller KD, Jemal A (2016) Cancer statistics. CA Cancer J Clin 66:7–30. https://doi.org/10.3322/caac.21332
Bode AM, Dong Z (2009) Cancer prevention research—then and now. Nat Rev Cancer 9:508–516. https://doi.org/10.1038/nrc2646
Morgan DO (2007) The cell cycle principles of control. New Science Press, London
Lah TT, Durán Alonso MB, Van Noorden CJ (2006) Antiprotease therapy in cancer: hot or not? Expert Opin Biol Ther 6:257–279. https://doi.org/10.1517/147125184.108.40.2067
Gondi CS, Rao JS (2013) Cathepsin B as a cancer target. Expert Opin Ther Targets 17:281–291. https://doi.org/10.1517/14728222.2013.740461
Michaud S, Gour BJ (1998) Cathepsin B inhibitors as potential anti-metastatic agents. Expert Opin Ther Pat 8:645–672. https://doi.org/10.1517/135437220.127.116.115
Lampe CM, Gondi CS (2014) Cathepsin B inhibitors for targeted cancer therapy. J Cancer Sci Ther 06:417–421. https://doi.org/10.4172/1948-5956.1000302
Aggarwal N, Sloane BF (2014) Cathepsin B: multiple roles in cancer. Proteom Clin Appl 8:427–437. https://doi.org/10.1002/prca.201300105
Rossi A, Deveraux Q, Turk B, Sali A (2004) Comprehensive search for cysteine cathepsins in the human genome. Biol Chem 385:363–372. https://doi.org/10.1515/BC.2004.040
Sloane BF, Moin K, Krepela E, Rozhin J (1990) Cathepsin B and its endogenous inhibitors: the role in tumor malignancy. Cancer Metastasis Rev 9:333–352. https://doi.org/10.1007/BF00049523
Gocheva V, Joyce JA (2007) Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle 6:60–64. https://doi.org/10.4161/cc.6.1.3669
Lakka SS, Gondi CS, Rao JS (2005) Proteases and glioma angiogenesis. Brain Pathol 15:327–341. https://doi.org/10.1111/j.1750-3639.2005.tb00118.x
Frlan R, Gobec S (2006) Inhibitors of cathepsin B. Curr Med Chem 13:2309–2327. https://doi.org/10.2174/092986706777935122
Kos J, Mitrović A, Mirković B (2014) The current stage of cathepsin B inhibitors as potential anticancer agents. Future Med Chem 6:1355–1371. https://doi.org/10.4155/fmc.14.73
Steverding D (2011) The cathepsin B-selective inhibitors CA-074 and CA-074Me inactivate cathepsin L under reducing conditions. Open Enzym Inhib J 4:11–16. https://doi.org/10.2174/1874940201104010011
Withana NP, Blum G, Sameni M et al (2012) Cathepsin B inhibition limits bone metastasis in breast cancer. Cancer Res 72:1199–1209. https://doi.org/10.1158/0008-5472.CAN-11-2759
Hatcher H, Planalp R, Cho J et al (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65:1631–1652. https://doi.org/10.1007/s00018-008-7452-4
Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin preclinical and clinical studies. Anticancer Res 23:363–398
Kocaadam B, Şanlier N (2017) Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr 57:2889–2895. https://doi.org/10.1080/10408398.2015.1077195
Lee W-H, Loo C-Y, Bebawy M et al (2013) Curcumin and its derivatives: their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol 11:338–378. https://doi.org/10.2174/1570159X11311040002
Aggarwal BB, Surh Y-J, Shishodia S (2007) The molecular targets and therapeutic uses of curcumin in health and disease. Springer, USA
Pavlin M, Repič M, Vianello R, Mavri J (2016) The chemistry of neurodegeneration: kinetic data and their implications. Mol Neurobiol 53:3400–3415. https://doi.org/10.1007/s12035-015-9284-1
Sharma RA, Gescher AJ, Steward WP (2005) Curcumin: the story so far. Eur J Cancer 41:1955–1968. https://doi.org/10.1016/j.ejca.2005.05.009
Cheng AL, Hsu CH, Lin JK et al (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high- risk or pre-malignant lesions. Anticancer Res 21:2895–2900
Sharma RA, Euden SA, Platton SL et al (2004) Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 10:6847–6854. https://doi.org/10.1158/1078-0432.CCR-04-0744
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818. https://doi.org/10.1021/mp700113r
Ravish I, Raghav N (2014) Curcumin as inhibitor of mammalian cathepsin B, cathepsin H, acid phosphatase and alkaline phosphatase: a correlation with pharmacological activities. Med Chem Res 23:2847–2855. https://doi.org/10.1007/s00044-013-0872-1
Trott O, Olson A (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461. https://doi.org/10.1002/jcc.21334.AutoDock
Krieger E, Darden T, Nabuurs SB et al. (2004) Making optimal use of empirical energy functions: force-field parameterization in crystal space. Proteins Struct Funct Bioinforma 57:678–683. https://doi.org/10.1002/prot.20251
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
Ahmadi S, Barrios Herrera L, Chehelamirani M et al. (2018) Multiscale modeling of enzymes: QM-cluster, QM/MM, and QM/MM/MD: a tutorial review. Int J Quantum Chem 118:e25558. https://doi.org/10.1002/qua.25558
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
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
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
Tirado-Rives J, Jorgensen WL (2008) Performance of B3LYP Density functional methods for a large set of organic molecules. J Chem Theory Comput 4:297–306. https://doi.org/10.1021/ct700248k
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 Account 120:215–241. https://doi.org/10.1007/s00214-007-0310-x
Zhao Y, Truhlar DG (2008) Density functionals with broad applicability in chemistry. Acc Chem Res 41:157–167. https://doi.org/10.1021/ar700111a
Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3093. https://doi.org/10.1021/cr9904009
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
Bader RFW (1990) Atoms in molecules: a quantum theory. Oxford University Press, Oxford
Popelier PLA, Bader RFW (1992) The existence of an intramolecular C-H–O hydrogen bond in creatine and carbamoyl sarcosine. Chem Phys Lett 189:542–548. https://doi.org/10.1016/0009-2614(92)85247-8
Cheeseman JR, Carroll MT, Bader RFW (1988) The mechanics of hydrogen bond formation in conjugated systems. Chem Phys Lett 143:450–458. https://doi.org/10.1016/0009-2614(88)87394-9
Popelier PLA (1998) Morphy98 a program written by PLA popelier with a contribution from RGA Bone. UMIST, Manchester
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 M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, 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 R, Pomelli C, 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 Gaussian 09 (2010) Revision B.01, Gaussian, Inc., Wallingford, CT
Jackson PA, Widen JC, Harki DA, Brummond KM (2017) Covalent modifiers: a chemical perspective on the reactivity of α, β-unsaturated carbonyls with thiols via hetero-michael addition reactions. J Med Chem 60:839–885. https://doi.org/10.1021/acs.jmedchem.6b00788
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 September 19, 2013).
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Pitchumani Violet Mary, C., Vijayakumar, S. & Shankar, R. Inhibition mechanism of cathepsin B by curcumin molecule: a DFT study. Theor Chem Acc 138, 21 (2019). https://doi.org/10.1007/s00214-018-2410-1
- Enzyme inhibition
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