ABSTRACT:
A comprehensive analysis and comparison of the phytochemicals present in Azadiracta indica for their potential in inhibiting MMPs, which are one of the major targets for treating cancer was carried out. Though several MMP inhibitors (MMPIs) were reported and tested, a better MMPI was not yet identified. Failure of these inhibitors in clinical trial leads to the use of nonspecific drugs as a treatment option which in turn worsens the condition by exhibiting severe side effects and poor prognosis. Structure-based molecular docking studies followed with analysis and comparison of binding affinity scores for the phytochemicals from A. indica was carried out. The resultant better scored compound was then subjected to molecular dynamic simulation to verify the energy change and its stability. This revealed N-[(5-chloro-2-pyridyl)carbamothioyl]thiophene-2-carboxamide; (4aS,10aR)-6-hydroxy-7-(2-hydroxy-1-methyl-ethyl)-1,1,4a-trimethyl-3,4,10,10a-tetrahydrophenanthrene-2,9-dione; 7-hydroxy-6-methoxy-chromen-2-one and 2-ethyl-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-2-ium-4-carbaldehyde as the potential MMPIs. They scored 79.874, 73.789, 66.214 and 64.211 respectively. These scores are better than the scores of commonly used anticancer drug 5-Fluorouracil and clinically tested MMPIs namely Doxycycline and Metastat respectively.
Cite this article:
Baby Joseph, Ariya S. S. Antineoplastic effect of Phytochemicals from Azadirachta indica in Inhibiting Anticancer Target - Matrix Metallopeptidases. Research J. Pharm. and Tech 2020; 13(3):1100-1106. doi: 10.5958/0974-360X.2020.00202.4
Cite(Electronic):
Baby Joseph, Ariya S. S. Antineoplastic effect of Phytochemicals from Azadirachta indica in Inhibiting Anticancer Target - Matrix Metallopeptidases. Research J. Pharm. and Tech 2020; 13(3):1100-1106. doi: 10.5958/0974-360X.2020.00202.4 Available on: https://rjptonline.org/AbstractView.aspx?PID=2020-13-3-7
REFERENCES:
1. Gialeli, C, Theocharis, A.D, Karamanos,
N.K, Roles of matrix metalloproteinases in cancer progression and their
pharmacological targeting. FEBS J. 278:1 (2011) 16-27.
2. Chien‐Yi Chan, Tzu‐Yuan Lin, Jim Jinn‐Chyuan Sheu, Wen‐Chieh Wu and
Chun‐Yin Huang. Matrix
metalloproteinase‐13 is a target gene of high‐mobility group box‐containing
protein 1 in modulating oral cancer cell invasion. Journal of Cellular
Physiology. 234:4 (2019) 4375-84.
3. M. Pavlaki, S. Zucker. Matrix
metalloproteinase inhibitors (MMPIs): the beginning of phase I or the
termination of phase III clinical trials. Cancer Metastasis Rev. 22: (2003)
177-203.
4. Fingleton,. MMPs as therapeutic
targets—still a viable option?. Semin Cell Dev Biol. 19: (2008) 61-68.
5. N. Sela-Passwell, A. Trahtenherts, A.
Kruger, I. Sagi. New opportunities in drug design of metalloproteinase
inhibitors: combination between structure–function experimental approaches and
systems biology. Expert Opin Drug Discov. 6: (2011), 527-542.
6. A. Dufour, C.M. Overall. Missing the
target: matrix metalloproteinase antitargets in inflammation and cancer. Trends
Pharmacol Sci. 34: (2013) 233-242.
7. Gemma
Shay, Conor C.Lynch, Barbara Fingleton.
Moving targets: Emerging roles for MMPs
in cancer progression and metastasis. Matrix Biology. 44 (2015) 200-206.
8. Mohammad A. Alzohairy. Therapeutics Role of Azadirachta indica
(Neem) and Their Active Constituents in Diseases Prevention and Treatment. Evidence-Based
Complementary and Alternative Medicine. 7382506 (2016) 1- 11.
9. Duke, James A. Dr. Duke's Phytochemical
and Ethnobotanical Databases" (Data Set). Ag Data Commons. (2016).
10. Kaushik S Hatti, Lakshmi Muralitharan,
Rajendra Hegde and Anil Kush. NeeMDB: Convenient Database for Neem Secondary
Metabolites. Bioinformation 10:5 (2014) 314-315.
11. Kim, S., Thiessen, P. A., Bolton, E. E.,
Chen, J., Fu, G., Gindulyte, A.,Bryant, S. H. PubChem Substance and Compound
databases. Nucleic acids research. 44:
(2016) D1202–D1213.
12. Harry E. Pence, Antony Williams. ChemSpider: An Online Chemical Information
Resource. J. Chem. Educ.
87:11; (2010) 1123-24.
13. Antoine Daina, Olivier Michielin and
Vincent Zoete. SwissADME: a free web tool to evaluate pharmacokinetics, druglikeness
and medicinal chemistry friendliness of small molecules. Scientific reports. 7:
(2017) 1-13.
14. Lipinski CA, Lombardo F, Dominy BW, Feeney
P. Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.
46: (2001) 3–26.
15. Berman,H.M. The Protein Data Bank: a
historical perspective. Acta Crystallographica.
64: (2008) 88-95.
16. Tochowicz, A., Goettig,
P., Evans, R., Visse, R., Shitomi, Y., Palmisano, R.,
Ito, N., Richter, K., Maskos, K.,
Franke, D., Svergun, D., Nagase, H., Bode, W.,
Itoh, Y. The Dimer Interface of
the Membrane Type 1 Matrix Metalloproteinase Hemopexin Domain crystal structure
and biological functions. J.Biol.Chem. 286:
(2011) 7587-7600.
17. BoscoK Ho and Robert Brasseur. The
Ramachandran plots of glycine and pre-proline. BMC Structural Biology. 5:
(2005) 1-4.
18. Brooks BR, Bruccoleri RE, Olafson BD,
States DJ, Swaminathan S, Karplus M, CHARMM: A program for macromolecular
energy, minimization and dynamic calculations. J Comput Chem. 4:2 (1983)
187-217.
19. Bingding Huang. MetaPocket: A Meta
Approach to Improve Protein Ligand Binding Site Prediction. OMICS A Journal of
Integrative Biology 13:4 (2009) 325-330.
20. Noel Vinay Thomas and Se-Kwon Kim.
Metalloproteinase Inhibitors: Status and Scope from Marine Organisms.
Biochemistry Research International. 845975: (2010) 1-10.
21. L. M. Coussens, B. Fingleton, and L. M.
Matrisian. Matrix metalloproteinase inhibitors and cancer: trials and
tribulations, Science. 295: (2002) 2387–2392.
22. Zhang and S.-K. Kim. Matrix
metalloproteinase inhibitors (MMPIs) from marine natural products: the current
situation and future prospects. Marine Drugs. 7: (2009) 71–84.
23. Nikeherpianti Lolok, Harlyanti Muthmainnah
Mashar, Itma Annah, Ahmad Saleh, Wa Ode Yuliastri and Muhammad Isrul.
Antidiabetic effect of the Combination of Garlic peel extract Allium sativum) and onion peel (Allium
cepa) in rats with oral glucose tolerance method. RJPT. 12:5(2019)0974-3618.
24. Ariya SS, Baby Joseph, S Vijayasrei, W
Hopper. Computational analysis of compounds from Ocimum sanctum for anticancer
activity against oral squamous cell carcinoma. AJPCR. 12:1(2019) 168-172.