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Current Drug Discovery Technologies


ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

A Computational Study of Famciclovir Derivatives Against Thymidine Kinase as a Molecular Target for the Development of Novel Anticancer Drugs via Suicide Gene Therapy Concepts

Author(s): Saravanan Thangavelu, Prabha Thangavelu*, Pradeep Kumar M.R., Sengotuvelu Singaravel, Lalitha Vivekanandan, Jagadeeswaran Murugesan and Sivakumar Thangavel

Volume 20, Issue 5, 2023

Published on: 13 June, 2023

Article ID: e090523216693 Pages: 12

DOI: 10.2174/1570163820666230509103455

Price: $65


Background: The viral thymidine kinase (TK) phosphorylates the antiviral medication famciclovir (FCV), which treats herpes simplex virus (HSV-TK). The phosphorylated FCV destroys the infected cells by preventing cellular DNA synthesis.

Objective: We hypothesize that FCV impurity, which is a related substance to FCV, should be efficient in killing cells independent of HSV-TK and is currently the most widely used suicide agent for gene therapy of cancer.

Methods: This study proposes the binding affinity of these derivatives for the active site of TK through molecular docking to a protein (PDB ID: 1W4R). The derivatives' reliability was ensured through the in-silico preliminary drug designing model by screening their Lipinski rule of five violations, if any, ADMET prediction for their profile using online tools. Using MOE 2009.10 computational software, we performed molecular docking of approximately 22 famciclovir derivatives alongside the famciclovir drug.

Results: Our results suggest that these derivatives are indicative of possible chemical stability irrespective of all the parameters used to evaluate the selected derivatives as a possible drug candidates for their cytotoxicity. FC20 (i.e., 2-(2-(2-((1-(9-(4-Acetoxy-3-(acetoxymethyl)butyl)-2-amino-9Hpurin- 8-yl)ethyl)amino)-9H-purin-9-yl)ethyl)propane-1,3-diyl diacetate) and FC21 (i.e., 2-Amino-1,9- dihydro-9-(4-hydroxybutyl)-6H-purin-6-one), showed maximum and minimum scores of -26.95 and - 7.21 kcal/mol, respectively when compared to famciclovir (-15.4122 kcal/mol).

Conclusion: Considering that there might be a cytotoxicity effect due to competition between protein TK and the suicidal gene of famciclovir derivatives. The outcome of the study proved that the FCV impurity could successfully modify an HSV-TK-dependent antiviral drug into an anti-tumor drug. Further, it can be used for the design and development of novel compounds of FCV impurity that could be cytotoxic agents if properly delivered to cancer cells.

Keywords: Suicide gene therapy, herpes simplex virus, thymidine kinase, famciclovir derivatives, molecular-docking, cancer therapy.

Graphical Abstract
Springer CJ, Niculescu-Duvaz I. Prodrug-activating systems in suicide gene therapy. J Clin Invest 2000; 105(9): 1161-7.
[] [PMID: 10791987]
Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: Paradigm for a prospective cancer control strategy. Cancer Res 1986; 46(10): 5276-81.
[PMID: 3019523]
Jiao LR, Havlik R, Nicholls J, Jensen SL, Habib NA. Suicide gene therapy in liver tumors. Methods Mol Med 2004; 90: 433-50.
[PMID: 14657577]
Debasis M. Famciclovir. xPharm: The comprehensive pharmacology reference. In: Enna SJ, David BB. Elsevier 2007; pp. 1-4.
Fillat C, Carrió M, Cascante A, Sangro B. Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: Fifteen years of application. Curr Gene Ther 2003; 3(1): 13-26.
[] [PMID: 12553532]
Shen Y, Nemunaitis J. Herpes Simplex Virus 1 (HSV-1) for cancer treatment. Cancer Gene Ther 2006; 13(11): 975-92.
[] [PMID: 16604059]
Jain RK. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 2005; 307(5706): 58-62.
[] [PMID: 15637262]
Munn L. Aberrant vascular architecture in tumors and its importance in drug-based therapies. Drug Discov Today 2003; 8(9): 396-403.
[] [PMID: 12706657]
a) Miller A. Human gene therapy comes to age. Nature 1992; 357(6378): 455-60.
b) Black ME, Newcomb TG, Wilson HM, Loeb LA. Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc Natl Acad Sci 1992; 93(8): 3525-9.
Dey D, Evans GR. Suicide gene therapy by herpes simplex virus-1 thymidine kinase (HSV-TK). In: You Y, Ed. Targets in Gene Therapy. London: IntechOpen 2011.
Frederick L. Moolten, Paula JM. Preemptive and therapeutic uses of suicide genes for cancer and leukemia. In: Edmund CL, Stanton LG, Eds. Gene Therapy of Cancer. (2nd ed.). Academic Press 2002; pp. 481-91.
Bora R, Jeyaprakash MR, Jubie S. Effect of anti-retroviral drug impurity/related substances on the ccr5 and/or cxcr4 receptors binding sites to revise resistance mechanisms in the clinical implications using molecular docking studies. Curr Drug Discov Technol 2022; 19(1): e140122192497.
[] [PMID: 33781190]
Famciclovir Available from : (Assessed on: 26.09.2022).
Prabha T, Aishwaryah P, Manickavalli E, et al. A chalcone annulated pyrazoline conjugates as a potent antimycobacterial agents: Synthesis and in silico molecular modeling studies. Res J Pharm Technol 2019; 12(8): 3857-65.
Thangavelu P, Thangavel S. Design, synthesis, and docking of sulfadiazine schiff base scaffold for their potential claim as INHA Enoyl-(Acyl-Carrier-Protein) reductase inhibitors. Asian J Pharm Clin Res 2018; 11(10): 233-7.
Kokoris MS, Black ME. Characterization of herpes simplex virus type 1 thymidine kinase mutants engineered for improved ganciclovir or acyclovir activity. Protein Sci 2002; 11(9): 2267-72.
[] [PMID: 12192082]
Birringer MS, Claus MT, Folkers G, Kloer DP, Schulz GE, Scapozza L. Structure of a type II thymidine kinase with bound dTTP. FEBS Lett 2005; 579(6): 1376-82.
[] [PMID: 15733844]
Kiruthiga N, Prabha T, Selvinthanuja C, Srinivasan K, Sivakumar T. Multidocking studies on 2-phenyl-4h-chromen-4-one hybrid and evaluation of anti-diabetic activity. J Pharm Sci 2018; 10(12): 3018.
Freund CT, Sutton MA, Dang T, Contant CF, Rowley D, Lerner SP. Adenovirus-mediated combination suicide and cytokine gene therapy for bladder cancer. Anticancer Res 2000; 20(3A): 1359-65.
[PMID: 10928044]
Rosolen A, Frascella E, Francesco C, et al. In vitro and in vivo antitumor effects of retrovirus-mediated herpes simplex thymidine kinase gene-transfer in human medulloblastoma. Gene Ther 1998; 5(1): 113-20.
[] [PMID: 9536272]
Huang Q, Xia Z, You Y, Pu P. Wild Type p53 gene sensitizes rat C6 glioma cells to HSV-TK/ACV treatment in vitro and in vivo. Pathol Oncol Res 2010; 16(4): 509-14.
[] [PMID: 20084481]
Fulci G, Chiocca EA. The status of gene therapy for brain tumors. Expert Opin Biol Ther 2007; 7(2): 197-208.
[] [PMID: 17250458]
Yao J, Zhang Y, Ramishetti S, Wang Y, Huang L. Turning an antiviral into an anticancer drug: Nanoparticle delivery of acyclovir monophosphate. J Control Release 2013; 170(3): 414-20.
[] [PMID: 23791977]
Nierode G, Kwon PS, Dordick JS, Kwon SJ. Cell-based assay design for high-content screening of drug candidates. J Microbiol Biotechnol 2016; 26(2): 213-25.
[] [PMID: 26428732]
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7(1): 42717.
[] [PMID: 28256516]
Jubie S, Durai U, Latha S, Ayyamperumal S, Wadhwani A, Prabha T. Repurposing of benzimidazole scaffolds for her2 positive breast cancer therapy: An in-silico approach. Curr Drug Res Rev 2021; 13(1): 73-83.
[] [PMID: 32955008]
Uckert W, Kammertöns T, Haack K, et al. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo. Hum Gene Ther 1998; 9(6): 855-65.

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