Virtual high-throughput screening (VHTS), three-dimensional quantitative structure- activity and relationship (3D-QSAR) and molecular docking studies of novel phyto-inhibtors of topoisomerase II alpha

Olawole Y.  Adeniran; Ayorinde  O; Metibemu; Samuel O.  Boboye

doi:10.30574/gscbps.2021.15.2.0099

Authors

Olawole Y. Adeniran Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria.
Ayorinde O Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria.
Metibemu Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria.
Samuel O. Boboye Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria.

DOI:

https://doi.org/10.30574/gscbps.2021.15.2.0099

Keywords:

Cancer, Topoisomerase II alpha, DNA replication, Etoposide, Phytochemicals, Three-Dimensional Quantitative Structure-Activity and Relationship (3D-QSAR).

Abstract

Topoisomerase II alpha catalyses and guides the unknotting of DNA by creating double transient breaks in the DNA using a conserved tyrosine as the catalytic residue. Topoisomerase II alpha has been shown to be overexpressed in numerous types of cancers and it is a target for multiple chemotherapeutic agents. Many DNA topoisomerase inhibitors have been identified from natural sources and have been reviewed in many reports as anticancer agents. In the present study, a total of 240 phytochemicals characterized from four reported anticancer plants (Anacardium occidentale, Andrographis paniculata, Cannabis sativa and Tinospora cordifolia) were obtained from literatures and screened against the binding pocket of topoisomerase II alpha. From the pool of phytochemicals only 7-o-methylcyanidin, 20-betaecdysone, Andropanoside and Palmatoside-G qualified as Phyto-compounds with good oral bioactivity when subjected to the Lipinski’s rule of five. Bioassay data containing the IC₅₀ of compounds screened against topoisomerase II alpha was used to generate a regression model using the 3D-QSAR techniques. A very viable model with R²= 0.954, adjusted R² = 0.908, Pearson R = 0.977, cross validation Q² = 0.851, Standard Error of Estimate = 0.125, F = (20.803, p < 0.05) and Durbin-Watson constant = 1.613 was obtained. The 3D-QSAR result shows that Andropanoside and 20-betaecdysone may be better inhibitors of topoisomerase II alpha catalytic site than the standard drug, Etoposide. To further confirm this, the molecular interactions of Andropanoside and 20-betaecdysone were compared to those of Etoposide using the ligand interaction interface of Maestro environment.

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References

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65: 87–108.

Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates and Trends–An Update. Cancer Epidemiol Biomarkers Prev. 2016; 25: 16–27.

Hejmadi M. How cancer arises. Introduction to Cancer Biology. Frederiksberg, Denmark: BoonBooks.com. 2010.

Hayflick L. Mortality and immortality at the cellular level. A Review Biochemistry. 1997; 62: 1180-1190.

Kaur S, Kaur S. Bacteriocins as Potential Anticancer Agents. Frontiers in pharmacology. 2015; 6: 272.

Pfister TD, Reinhold WC, Agama K, Gupta S, Khin SA, Kinders RJ, Parchment RE, Tomaszewski JE, Doroshow JH, Pommier Y. Topoisomerase I level in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity. Mol. Cancer Ther. 2009; 8(7): 1878-1884.

Ashour ME, Atteya R, El-Khamisy SF. Topoisomerase mediated chromosomal break repair: an emerging player in many games. Nat. Rev. Cancer. 2015; 15(3): 137-151.

Chen T, Sun Y, Ji P, Kopetz S, Zhang W. Topoisomerase II alpha in chromosome instability and personalized cancer therapy. Oncogene. 2015; 34(31): 4019-4031.

Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem. 2001; 70: 369–413.

Depowski PL, Rosenthal SI, Brien TP, et al. Topoisomerase II alpha expression in breast cancer: correlation with outcome variables. Mod Pathol. 2000; 13: 542–547.

Villman K, Ståhl E, Liljegren G, Tidefelt U, Karlsson MG. Topoisomerase II-alpha expression in different cell cycle phases in fresh human breast carcinomas. Mod Pathol. 2002; 15(5): 486-491.

Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nature Reviews Cancer. 2009; 9: 338–350.

Drake FH, Hoffmann GA, Mong SM, Bartus JO, Hertzberg RP, Johnson RK, Mattern MR, Mirabelli CK. In vitro intracellular inhibition of topoisomerase II by the antitumor agent merbarone. Cancer Res. 1989; 49(10): 2578-2583.

Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 2010; 17(5): 421-433.

Jain CK, Majumdera HK, Roy Choudhury BS. Natural Compounds as Anticancer Agents Targeting DNA Topoisomerases. Current Genomics. 2017; 18(1): 75-92.

Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer. 2006; 6(10): 789-802.

Baikar S, Malpathak N. Secondary metabolites as DNA topoisomerase inhibitors: A new era towards designing of anticancer drugs. Pharmacognosy Review. 2010; 4(7): 12-26.

Bailly C. Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. Chem. Rev. 2013; 112(7): 3611-3640.

Pommier Y. Drugging topoisomerases: lessons and challenges. ACS Chem. Biol. 2013; 8(1): 82-95.

Desai AG, Qazi GN, Ganju RK, El-Tamer M, Singh J, Saxena AK, Bedi YS, Aneja SC, Bhat HK. Medicinal plants and Cancer Chemoprevention. Curr Drug Metab. 2008; 9(7): 581-591.

Souza NC, Oliveira JM, Morrone MS, Albanus RD, Amarante MSM, Camillo CS, Langassner SMZ, Gelain DPG, Moreira JCF, Dalmolin RJS, Pasquali MAB. Antioxidant and Anti-Infammatory Properties of Anacardium occidentale Leaf Extract. Evidence-Based Complementary and Alternative Medicine. 2017 Jan 1: 2017

Guzman M. Cannabinoids: potential anticancer agents. Nat Rev Cancer. 2003; 3: 745-55.

Velasco G, Sánchez C, Guzmán M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer. 2012; 12: 436–444.

Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 2008; 9: 40.

Li H, Leung KS, Wong MH, Ballester PJ. Correcting the impact of Docking pose generation error on binding affinity prediction. BMC Bioinformatics. 2016; 17(11): 308.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development. Advanced Drug Delivery Reviews. 2001; 46: 3–26.

Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM. The Structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. Journal of molecular biology. 2012; 424(3-4): 109-24.