Inhibition mechanism of cathepsin B by curcumin molecule: a DFT study
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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.
KeywordsCancer DFT Enzyme inhibition Phytochemical compound Quantum chemical calculation
Quantum theory of atoms in molecules
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).
Compliance with ethical standards
Conflict of interest
No conflict of interest exists in the submission of this manuscript, and this manuscript is approved by all authors for publication.
- 3.Morgan DO (2007) The cell cycle principles of control. New Science Press, LondonGoogle Scholar
- 12.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 CrossRefPubMedGoogle Scholar
- 24.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 21:2895–2900Google Scholar
- 25.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 CrossRefPubMedGoogle Scholar
- 36.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 CrossRefGoogle Scholar
- 40.Bader RFW (1990) Atoms in molecules: a quantum theory. Oxford University Press, OxfordGoogle Scholar
- 43.Popelier PLA (1998) Morphy98 a program written by PLA popelier with a contribution from RGA Bone. UMIST, ManchesterGoogle Scholar
- 44.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, CTGoogle Scholar