Anticancer screening of medicinal plant phytochemicals against Cyclin-Dependent Kinase-2 (CDK2): An in-silico approach

Wajahat Khan, Usman Ali Ashfaq, Sadia Aslam, Sidra Saif, Tehzeeb Aslam, Kishver Tusleem, Arooma Maryam, Muhammad Tahir ul Qamar

Abstract


Background: Cyclin-Dependent Kinase-2 (CDK2) is a member of serine/threonine protein kinases family and plays an important role in regulation of various eukaryotic cell division events. Over-expression of CDK2 during cell cycle may lead to several cellular functional aberrations including diverse types of cancers (lung cancer, primary colorectal carcinoma, ovarian cancer, melanoma and pancreatic carcinoma) in humans. Medicinal plants phytochemicals which have anticancer potential can be used as an alternative drug resource.

Methods: This study was designed to find out anticancer phytochemicals from medicinal plants which could inhibit CDK2 with the help of molecular docking technique. Molecular Operating Environment (MOE v2009) software was used to dock 2300 phytochemicals in this study.

Results: The outcome of this study shows that four phytochemicals Kushenol T, Remangiflavanone B, Neocalyxins A and Elenoside showed the lowest S-score (-17.83, -17.57, -17.26, -17.17 respectively) and binds strongly with all eight active residues Tyr15, Lys33, Ileu52, Lys56, Leu78, phe80, Asp145 and Phe146 of CDK2 binding site. These phytochemicals could successfully inhibit the CDK2.

Conclusion: These phytochemicals can be considered as potential anticancer agents and used in drug development against CDK2. We anticipate that this study would pave way for phytochemical based novel small molecules as more efficacious and selective anti-cancer therapeutic compounds.


Full Text:

PDF

References


Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, (2011); 144(5): 646-674.

Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Proliferation, (2003); 36(3): 131-149.

Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene, (2009); 28(33): 2925.

Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Reviews Cancer, (2009); 9(3): 153.

Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nature Reviews Drug Discovery, (2009); 8(7): 547-566.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer Journal for Clinicians, (2016); 66(1): 7-30.

McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clinics in Liver Disease, (2015); 19(2): 223-238.

Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians, (2016); 66(4): 271-289.

Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, et al. Thyroid cancer mortality and incidence: a global overview. International Journal of Cancer, (2015); 136(9): 2187-2195.

Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nature Reviews Drug Discovery, (2015); 14(2): 130.

Varbanov HP, Kuttler F, Banfi D, Turcatti G, Dyson PJ. Repositioning approved drugs for the treatment of problematic cancers using a screening approach. PloS One, (2017); 12(2): e0171052.

Kinch MS. An analysis of FDA-approved drugs for oncology. Drug Discovery Today, (2014); 19(12): 1831-1835.

Wu P, Nielsen TE, Clausen MH. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discovery Today, (2016); 21(1): 5-10.

Sherr CJ, Bartek J. Cell Cycle–Targeted Cancer Therapies, (2017); 1: 41-57.

Shukla S, Mehta A. Anticancer potential of medicinal plants and their phytochemicals: a review. Brazilian Journal of Botany, (2015); 38(2): 199-210.

Avni GD, Ghulam NQ, Ramesh KG, Mahmoud E-T, Jaswant S, et al. Medicinal Plants and Cancer Chemoprevention. Current Drug Metabolism, (2008); 9(7): 581-591.

David MP, Patricia V, Georgina C-d-S, Natercia T, Paula BA. Plant Secondary Metabolites in Cancer Chemotherapy: Where are We? Current Pharmaceutical Biotechnology, (2012); 13(5): 632-650.

Chemical Computing Group ULC (2013) Molecular Operating Environment (MOE) 09. 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2017.

Mumtaz A, Ashfaq UA, ul Qamar MT, Anwar F, Gulzar F, et al. MPD3: a useful medicinal plants database for drug designing. Natural Product Research, (2017); 31(11): 1228-1236.

Ashfaq UA, Mumtaz A, Qamar Tu, Fatima T. MAPS Database: Medicinal plant Activities, Phytochemical and Structural Database. Bioinformation, (2013); 9(19): 993-995.

Irwin JJ, Shoichet BK. ZINC− a free database of commercially available compounds for virtual screening. Journal of Chemical Information and Modeling, (2005); 45(1): 177-182.

Bolton EE, Wang Y, Thiessen PA, Bryant SH. PubChem: integrated platform of small molecules and biological activities. Annual Reports in Computational Chemistry, (2008); 4217-241.

Betzi S, Alam R, Martin M, Lubbers DJ, Han H, et al. Discovery of a Potential Allosteric Ligand Binding Site in CDK2. ACS Chemical Biology, (2011); 6(5): 492-501.

Deng Y, Lee JP, Tianasoa-Ramamonjy M, Snyder JK, Des Etages SA, et al. New Antimicrobial Flavanones from Physena madagascariensis. Journal of Natural Products, (2000); 63(8): 1082-1089.

Minh Giang P, Tong Son P, Matsunami K, Otsuka H New Diarylheptanoids from Alpinia pinnanensis. Chemical and Pharmaceutical Bulletin, (2005); 53(10): 1335-1337.

Navarro E, Alonso SJ, Trujillo J, Jorge E, Pérez C. Central nervous activity of elenoside. Phytomedicine, (2004); 11(6): 498-503.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25.1. Advanced Drug Delivery Reviews, (2001); 46(1): 3-26.

Hanahan D, Weinberg RA. The Hallmarks of Cancer. Cell, 100(1): 57-70.

Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature, (2009); 458(7239): 719.

Ahmed B, Ashfaq UA, ul Qamar MT, Ahmad M. Anticancer potential of phytochemicals against breast cancer: Molecular docking and simulation approach. Bangladesh Journal of Pharmacology, (2014); 9(4): 545-550.

O'leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nature Reviews Clinical Oncology, (2016); 13(7): 417-430.

Pezzuto JM. Plant-derived anticancer agents. Biochemical Pharmacology, (1997); 53(2): 121-133.

ul Qamar MT, Mumtaz A, Ashfaq UA, Adeel MM, Fatima T. Potential of plant alkaloids as dengue ns3 protease inhibitors: Molecular docking and simulation approach. Bangladesh Journal of Pharmacology, (2014); 9(3): 262-267.

ul Qamar MT, Mumtaz A, Rabbia Naseem AA, Fatima T, Jabbar T, et al. Molecular docking based screening of plant flavonoids as dengue NS1 inhibitors. Bioinformation, (2014); 10(7): 460.

ul Qamar T, Mumtaz A, Ashfaq UA, Azhar S, Fatima T, et al. Computer aided screening of phytochemicals from garcinia against the dengue NS2B/NS3 protease. Bioinformation, (2014); 10(3): 115.

Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends in Pharmacological Sciences, (2015); 36(7): 422-439.

Lima GM, Quintans-Júnior LJ, Thomazzi SM, Almeida EMSA, Melo MS, et al. Phytochemical screening, antinociceptive and anti-inflammatory activities of Chrysopogon zizanioides essential oil. Revista Brasileira de Farmacognosia, (2012); 22443-450.


Refbacks

  • There are currently no refbacks.