DOI: https://doi.org/10.14710/jksa.25.3.87-96

Computational Studies of Thiourea Derivatives as Anticancer Candidates through Inhibition of Sirtuin-1 (SIRT1)

1Faculty of Pharmacy, Universitas Bakti Tunas Husada, Tasikmalaya, West Java, Indonesia

2Department of Pharmacy, Faculty of Health Science, Universitas Perjuangan, Tasikmalaya 46115, West Java, Indonesia

3Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia

Received: 7 Dec 2021; Revised: 28 Feb 2022; Accepted: 8 Mar 2022; Published: 31 Mar 2022.
Open Access Copyright 2022 Jurnal Kimia Sains dan Aplikasi under http://creativecommons.org/licenses/by-sa/4.0.

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Abstract
Cancer is a disease that starts from the uncontrolled growth of abnormal cells in the organs or tissues of the body, which is the second leading cause of death in the world. One of the targets in discovering and developing anticancer drugs is Sirtuin-1. SIRT1 can act as a tumor suppressor or tumor promoter depending on its target in a particular signalling pathway or on particular cancer. This study aimed to study the interaction of a thiourea derivative with SIRT1 (PDB ID:4I5I) through its inhibition of histone deacetylase. Research has been carried out in silico with molecular docking (MGLTools.1.5.6) and molecular dynamics (Desmond 2019) of three thiourea derivatives to the receptor. In addition, pharmacokinetic parameters, toxicity, and selection of Lipinski's Rule of Five were also tested. Molecular docking results showed that compound b ([2-(methylcarbamothioylcarbamoyl)phenyl]benzoate) had the lowest ∆G value of −9.29 kcal/mol with a KI value of 0.156 µM compared to other thiourea derivatives and was proven by molecular dynamics tests for 30 ns and amino acids that play an active role in the interaction include the residue PheA:297. In terms of pharmacokinetics and toxicity, compound b is better than natural ligands. Compound b is predicted to be used as an anticancer candidate through further research.
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Keywords: molecular dynamics; cancer; molecular docking; sirtuin-1; thiourea
Funding: Bakti Tunas Husada College of Health Sciences; Universitas Perjuangan; Universitas Indonesia

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Language : EN
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  1. World Health Organization, Cancer, World Health Organization, 2021
  2. J. Ferlay, M. Ervik, F. Lam, M. Colombet, L. Mery, Global Cancer Observatory: Cancer Today, International Agency for Research on Cancer, World Health Organization, 2020
  3. Kementerian Kesehatan Republik Indonesia, in, Pusat Data dan Informasi Kementerian Kesehatan Republik Indonesia, Jakarta, 2015,
  4. Birsen Elibol, Ulkan Kilic, High levels of SIRT1 expression as a protective mechanism against disease-related conditions, Frontiers in Endocrinology, 9, 614, (2018), 1-7 https://doi.org/10.3389/fendo.2018.00614
  5. Zhenghong Lin, Deyu Fang, The roles of SIRT1 in cancer, Genes & Cancer, 4, 3-4, (2013), 97-104 https://doi.org/10.1177/1947601912475079
  6. Wenwen Zang, Yujun Hao, Zhenghe Wang, Weiping Zheng, Novel thiourea-based sirtuin inhibitory warheads, Bioorganic & Medicinal Chemistry Letters, 25, 16, (2015), 3319-3324 https://doi.org/10.1016/j.bmcl.2015.05.058
  7. Carmen Avendaño, J. Carlos Menendez, Medicinal chemistry of anticancer drugs, 2nd ed., Elsevier, Netherlands, 2015
  8. Pillaiyar Thanigaimalai, Ki-Cheul Lee, Vinay K. Sharma, Cheonik Joo, Won-Jea Cho, Eunmiri Roh, Youngsoo Kim, Sang-Hun Jung, Structural requirement of phenylthiourea analogs for their inhibitory activity of melanogenesis and tyrosinase, Bioorganic & Medicinal Chemistry Letters, 21, 22, (2011), 6824-6828 https://doi.org/10.1016/j.bmcl.2011.09.024
  9. Ali Sohail Farooqi, Jun Young Hong, Ji Cao, Xuan Lu, Ian Robert Price, Qingjie Zhao, Tatsiana Kosciuk, Min Yang, Jessica Jingyi Bai, Hening Lin, Novel lysine-based thioureas as mechanism-based inhibitors of Sirtuin 2 (SIRT2) with anticancer activity in a colorectal cancer murine model, Journal of Medicinal Chemistry, 62, 8, (2019), 4131-4141 https://doi.org/10.1021/acs.jmedchem.9b00191
  10. Dini Kesuma, Bambang Tri Purwanto, Marcellino Rudyanto, Synthesis and anticancer evaluation of N-benzoyl-N’phenyltiourea derivatives againts human breast cancer cells (T47D), Journal of Chinese Pharmaceutical Sciences, 29, 2, (2019), 123-129 http://dx.doi.org/10.5246/jcps.2020.02.010
  11. Suko Hardjono, Tri Widiandani, Bambang Tri Purwanto, Anindi L. Anindi, Molecular docking of N-benzoyl-N’-(4-fluorophenyl) thiourea derivatives as anticancer drug candidate and their ADMET prediction, Research Journal of Pharmacy and Technology, 12, 5, (2019), 2160-2166 http://dx.doi.org/10.5958/0974-360X.2019.00359.7
  12. Dini Kesuma, Harry Santosa, Sintesis Senyawa 2, 4-diklorobenzoiltiourea dari 2, 4-diklorobenzoil klorida dan Tiourea Sebagai Calon Obat Central Nervous System Depressant Melalui Proses Refluks, Seminar Nasional Teknik Kimia Indonesia, Bandung, 2009
  13. Fatma Karipcin, Murat Atis, Bahtiyar Sariboga, Hasan Celik, Murat Tas, Structural, spectral, optical and antimicrobial properties of synthesized 1-benzoyl-3-furan-2-ylmethyl-thiourea, Journal of Molecular Structure, 1048, (2013), 69-77 https://doi.org/10.1016/j.molstruc.2013.05.042
  14. Wukun Liu, Jinpei Zhou, Tong Zhang, Haiyang Zhu, Hai Qian, Huibin Zhang, Wenlong Huang, Ronald Gust, Design and synthesis of thiourea derivatives containing a benzo [5, 6] cyclohepta [1, 2-b]pyridine moiety as potential antitumor and anti-inflammatory agents, Bioorganic & Medicinal Chemistry Letters, 22, 8, (2012), 2701-2704 https://doi.org/10.1016/j.bmcl.2012.03.002
  15. G. Kirishnamaline, J. Daisy Magdaline, T. Chithambarathanu, D. Aruldhas, A. Ronaldo Anuf, Theoretical investigation of structure, anticancer activity and molecular docking of thiourea derivatives, Journal of Molecular Structure, 1225, 129118, (2021), 1-24 https://doi.org/10.1016/j.molstruc.2020.129118
  16. Harry Santosa, Dini Kesuma, Aktivitas Antikanker Senyawa N-Etil-N-Feniltiourea secara In Silico dan In Vitro Pada Sel Kanker Payudara T47D dan Selektivitasnya pada Sel Normal Vero, Kongres XX & Pertemuan Ilmiah Tahunan Ikatan Apoteker Indonesia, Jakarta, 2018
  17. Reem A. K. Al-Harbi, Marwa A.M. Sh. El-Sharief, Samir Y. Abbas, Synthesis and anticancer activity of bis-benzo [d][1, 3] dioxol-5-yl thiourea derivatives with molecular docking study, Bioorganic Chemistry, 90, (2019), 1-9 https://doi.org/10.1016/j.bioorg.2019.103088
  18. Bachwani Mukesh, Kumar Rakesh, Molecular docking: a review, International Journal of Research in Ayurveda & Pharmacy, 2, 6, (2011), 1746-1751
  19. Md. Mushtaque, Meriyam Jahan, Murtaza Ali, Md Shahzad Khan, Mohd Shahid Khan, Preeti Sahay, Ashwani Kesarwani, Synthesis, characterization, molecular docking, DNA binding, cytotoxicity and DFT studies of 1-(4-methoxyphenyl)-3-(pyridine-3-ylmethyl) thiourea, Journal of Molecular Structure, 1122, (2016), 164-174 https://doi.org/10.1016/j.molstruc.2016.05.087
  20. Tero Huhtiniemi, Tiina Suuronen, Valtteri M. Rinne, Carsten Wittekindt, Maija Lahtela-Kakkonen, Elina Jarho, Erik A. A. Wallén, Antero Salminen, Antti Poso, Jukka Leppänen, Oxadiazole-carbonylaminothioureas as SIRT1 and SIRT2 inhibitors, Journal of Medicinal Chemistry, 51, 15, (2008), 4377-4380 https://doi.org/10.1021/jm800639h
  21. Ruswanto Ruswanto, Richa Mardianingrum, Tresna Lestari, Tita Nofianti, Siswandono Siswandono, 1-(4-Hexylbenzoyl)-3-methylthiourea, Molbank, 2018, 3, (2018), https://doi.org/10.3390/M1005
  22. Ruswanto Ruswanto, Amir M. Miftah, Daryono H. Tjahjono, Siswandono Siswandono, In silico study of 1-benzoyl-3-methylthiourea derivatives activity as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor candidates, Chemical Data Collections, 34, 100741, (2021), 1-33 https://doi.org/10.1016/j.cdc.2021.100741
  23. Amir M. Miftah, Daryono H. Tjahjono, Synthesis and in vitro Cytotoxicity of 1-Benzoyl-3-methyl Thiourea Derivatives, Procedia Chemistry, 17, (2015), 157-161 https://doi.org/10.1016/j.proche.2015.12.105
  24. David S. Goodsell, Garrett M. Morris, Arthur J. Olson, Automated docking of flexible ligands: applications of AutoDock, Journal of Molecular Recognition, 9, 1, (1996), 1-5 https://doi.org/10.1002/(SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6
  25. Xun Zhao, Dagart Allison, Bradley Condon, Feiyu Zhang, Tarun Gheyi, Aiping Zhang, Sheela Ashok, Marijane Russell, Iain MacEwan, Yuewei Qian, The 2.5 Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition, Journal of Medicinal Chemistry, 56, 3, (2013), 963-969 https://doi.org/10.1021/jm301431y
  26. Ruswanto Ruswanto, Richa Mardianingrum, Siswandono Siswandono, Dini Kesuma, Reverse docking, molecular docking, absorption, distribution, and toxicity prediction of artemisinin as an anti-diabetic candidate, Molekul, 15, 2, (2020), 88-96 https://doi.org/10.20884/1.jm.2020.15.2.579
  27. Richa Mardianingrum, Sri Rezeki Nur Endah, Eddy Suhardiana, Ruswanto Ruswanto, Siswandono Siswandono, Docking and molecular dynamic study of isoniazid derivatives as anti-tuberculosis drug candidate, Chemical Data Collections, 32, 100647, (2021), 1-11 https://doi.org/10.1016/j.cdc.2021.100647
  28. Ruswanto Ruswanto, Mardhiah Mardhiah, Richa Mardianingrum, Korry Novitriani, Sintesis dan Studi In Silico Senyawa 3-Nitro-N'-[(Pyridin-4-Yl) Carbonyl] Benzohydrazide sebagai Kandidat Antituberkulosis, Chimica et Natura Acta, 3, 2, (2015), 54-61 https://doi.org/10.24198/cna.v3.n2.9183
  29. Karisma Enggar Saputri, Nurul Fakhmi, Erwinda Kusumaningtyas, Dedy Priyatama, Broto Santoso, Docking molekular potensi anti diabetes melitus tipe 2 turunan zerumbon sebagai inhibitor aldosa reduktase dengan autodock-vina, Chimica et Natura Acta, 4, 1, (2016), 16-20 https://doi.org/10.24198/cna.v4.n1.10443
  30. Oleg Trott, Arthur J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, Journal of Computational Chemistry, 31, 2, (2010), 455-461 https://doi.org/10.1002/jcc.21334
  31. Sumit Kumar, Prem Prakash Sharma, Uma Shankar, Dhruv Kumar, Sanjeev K. Joshi, Lindomar Pena, Ravi Durvasula, Amit Kumar, Prakasha Kempaiah, Poonam, Discovery of new hydroxyethylamine analogs against 3CLpro protein target of SARS-CoV-2: Molecular docking, molecular dynamics simulation, and structure–activity relationship studies, Journal of Chemical Information and Modeling, 60, 12, (2020), 5754-5770 https://doi.org/10.1021/acs.jcim.0c00326
  32. Larisa Ivanova, Jaana Tammiku-Taul, Alfonso T. García-Sosa, Yulia Sidorova, Mart Saarma, Mati Karelson, Molecular dynamics simulations of the interactions between glial cell line-derived neurotrophic factor family receptor GFRα1 and small-molecule ligands, ACS Omega, 3, 9, (2018), 11407-11414 https://doi.org/10.1021/acsomega.8b01524
  33. Chetan Chintha, Antonio Carlesso, Adrienne M. Gorman, Afshin Samali, Leif A. Eriksson, Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1, RSC Advances, 10, 1, (2020), 367-375 https://doi.org/10.1039/C9RA08047C
  34. Nursalam Hamzah, Afrisusnawati Rauf, Ariwanti Ariwanti, Studi hubungan kuantitatif struktur-aktifitas (hksa)senyawa turunan 4-aminoquinolin pirimidin, docking molekul, penelusuran farmakofor, virtual screening, uji toksisitas, dan profil farmakokinetik sebagai antimalaria secara in silico, Jurnal Farmasi UIN Alauddin Makassar, 3, 4, (2017), 176-186
  35. Nursamsiar Nursamsiar, Alprida Tandi Toding, Akbar Awaluddin, Studi in silico senyawa turunan analog kalkon dan pirimidin sebagai antiinflamasi: Prediksi absorpsi, distribusi, dan toksisitas, Pharmacy: Jurnal Farmasi Indonesia (Pharmaceutical Journal of Indonesia), 13, 1, (2016), 92-100
  36. Gita Syahputra, L. Ambarsari, T. Sumaryada, Simulasi docking kurkumin enol, bisdemetoksikurkumin dan analognya sebagai inhibitor enzim12-lipoksigenase, Jurnal Biofisika, 10, 1, (2014), 55-67
  37. Richa Mardianingrum, Muhammad Yusuf, Maywan Hariono, Amira Mohd Gazzali, Muchtaridi Muchtaridi, α-Mangostin and its derivatives against estrogen receptor alpha, Journal of Biomolecular Structure and Dynamics, (2020), 1-14 https://doi.org/10.1080/07391102.2020.1841031

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