Research Journal of Pharmacy and Technology

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Molecular Docking of N-benzoyl-N'-(4-fluorophenyl) thiourea Derivatives as Anticancer Drug Candidate and Their ADMET Prediction


Affiliations
1 Department of Pharmaceutical Chemistry, Universitas Airlangga, Surabaya 60286, Indonesia
2 Delima Persada School of Health Sciences, Gresik, Indonesia
     

   Subscribe/Renew Journal


The pharmacophore group found in N-benzoyl-N’-(4-fluorophenyl) thiourea is the same as the urea derivative which has anti-cancer activity, such as hydroxyurea. Because of the presence of these pharmacophore groups, this compound is worthy of being used as parent compound for further development through structural modification. Structural modification as an effort to design the new drug is done by changing the substituted group, which will cause changes in physicochemical properties. The change in physicochemical properties can affect the pharmacokinetics process, toxicity and activity of each compound that can be predicted through molecular modeling. The aims of this present study are to obtain the N-benzoyl-N'-(4-fluorophenyl) thiourea derivatives which is predicted to have the best anticancer activity and is not toxic based on the in silico approach. One of the mechanism of action of the N-benzoil- N'-(4-fluorophenyl) thiourea derivative as an anti-cancer is to inhibit the Sirtuin1 enzyme (SIRT1). The inhibition of the enzyme causes over expression of p53 which is the gene responsible for negative regulation of the cell cycle by using the Chem Bio Draw Ultra 13.0 program which can predict physico-chemical properties of Log P, MR and Etot. Pharmacokinetic properties (ADME) and toxicity were determined using the online pkCSM program. The in silico test is carried out by documenting compounds which will be predicted by the target enzyme SIRT1 with PDB ID: 4I5I. Documentation results in the form of bond energy which is illustrated by the value of the Rerank Score (RS), using the MVD program (Molegro Virtual Docker). Compounds that have small RS values are predicted to have a large activity. From the results of the in silico test using the MVD program and the online pkCSM program it can be seen that 4 (four) N-benzoyl-N'-(4-fluorophenyl)thiourea derivatives are predicted to have good pharmacokinetics (ADME) properties, causing relatively low toxicity except N-4-trifluoromethyl-benzoyl-N’-(4-fluorophenyl)thiourea which can cause hepatotoxics. All compounds have cytotoxic activity greater than the comparative ligand 4I5_601. Compounds of N-4-chlorobenzoyl-N'-(4-fluorophenyl) thiourea are compounds that are predicted to have the most activity and are not toxic.

Keywords

Molecular Modeling, N-Benzoyl-N’-(4-Fluorophenyl) Thiourea, Physico-Chemistry, ADME Prediction.
Subscription Login to verify subscription
User
Notifications
Font Size


  • Siswandono. Pengembangan Obat. In : Siswandono. Kimia Medisinal 1. Surabaya : Airlangga University Press. 2016

  • Hardjono, S. Modifikasi struktur 1-(benzoiloksi)urea dan hubungan kuantitatif struktur-aktivitas sitotoksiknya. Disertasi . Surabaya: Fakultas Farmasi Universitas Airlangga. 2012

  • Hardjono S, Siswandono, Purwanto, Darmanto W. Quantitative Structure-Cytotoxic Activity Relationship 1-(Benzoyloxy)urea and Its Derivative, Current Drug Discovery Technology. , 2016; 13(2): 101-108.

  • Schlick T. Molecular Modeling and Simulation, An Interdisciplinary Guide. 2nd ed., New York: Springer Science+Business Medi. 2010

  • Venkatesh Kamath, Aravinda Pai. Application of Molecular Descriptors in Modern Computational Drug Design –An Overview. Research J. Pharm. and Tech. 2017; 10(9): 3237-3241.

  • Anwesha Barua, Keerthi Kesavan, Sivaraman Jayanthi. Molecular Docking Studies of Plant Compounds to Identify Efficient Inhibitors for Ovarian Cancer. Research J. Pharm. and Tech 2018; 11(9): 3811-3815.

  • Hinchliffe A. Molecular Modeling for Beginners. 2nd ed., Chichester: John Wiley and Sons Ltd. 2008

  • Siswandono. Pengembangan Obat Baru, Airlangga University Press, Surabaya. 2016.

  • Soumya Khare, Amit Alexander, Ajazuddin, Nisha Amit. Biomedical Applications of Nanobiotechnology for Drug Design, Delivery and Diagnostics. Research J. Pharm. and Tech. 7(8): August 2014 Page 915-925.

  • Prem Shankar Misra, V. Ravichandiran, M. Vijey Aanandhi. Design, Synthesis and In Silico Molecular Docking Study of N-carbamoyl-6-oxo-1-phenyl-1, 6-dihydropyridine-3-carboxamide derivatives as Fibroblast growth factor 1 inhibitor. Research J. Pharm. and Tech. 2017; 10(8): 2527-2534.

  • Jenzen F. Introduction to Computational Chemistry, 2nd Ed, Odense, Denmark, 2007: 415-416.

  • Habeela Jainab N, Mohan Maruga Raja. In Silico Molecular Docking Studies on the Chemical Constituents of Clerodendrum phlomidis for its Cytotoxic Potential against Breast Cancer Markers. Research J. Pharm. and Tech 2018; 11(4): 1612-1618.

  • WHO. http://www.who.int/mediacentre/factsheets/fs297/en/. 2012. Download at 28 Juli 2015

  • Myungsun Yi, Young Mi Ryu. The Effects of Breast Health Education in Women with Breast Cancer. Research J. Pharm. and Tech. 2017; 10(7): 2295-2302.

  • Saeed, S., Rashid, N., Jones, P. G., Ali, M., and Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. European Journal of Medicinal Chemistry. 2010; 45:1323–1331

  • Li, H., Yan, T., Yang, Y., Shi, L., Zhou, C., and Zhu, H. Synthesis and structure–activity relationships of N-benzyl-N- (X-2-hydroxybenzyl)-N0-phenylureas and thioureas as antitumor agents. Bioorganic and Medicinal Chemistry. 2010; 18:305–313

  • Dai, Y., Hartandi, K., Soni, N.B., Pease, L.J., Reuter, D.R., Olson, A.M., Osterling, D.J., Doktor, S.Z., Albert, D.H., Bouska, J.J., Glaser, K.B., Marcotte, P.A., Stewart, K.D., Davidsen, S.K., and Michaelides, M.R. Identification of aminopyrazolo-pyridine ureas as potent VEGFR-PDGFR multitargeted kinase inhibitors, Bioorganic and Medicinal Chemistry Letters. 2008; 18:386-390.

  • Usui, T., Ban, H.S., Kawada, J., Hirokawa, T., and Nakamura, H. Discovery of indenopyrazoles as EGFR and VEGFR-2 tyrosine kinase inhibitors by in silico high-throughput screening. Bioorganic and Medicinal Chemistry Letters. 2008; 18: 285-288

  • Curtin, M.L., Frey, R.R.,Heyman, H.R., Soni, N.B., Marcotte, P.A., Pease, L.J.,Glaser, K.B., Magoc, T.J., Tapang, P., Albert, D.H., Osterling, D.J., Olson, A.M.,Bouska, J.J., Guan, Z., Preusser, L.C., Polakowski, J.S., Stewart, K.D., Tse, C.,Davidsen, S.K., Michaelides, M.R. Thienopyridine ureas as dual inhibitors of the VEGF and Aurora kinase families. Bioorganic and Medicinal Chemistry Letters. 2012; 22: 3208-3212.

  • Ruswanto, Siswandono, Richa,M., Tita, N., Tresna, L. Molecular Docking of 1-Benzoyl-3-methylthiourea as Anti Cancer Candidate and Its Absorption, Distribution, and Toxicity Prediction, Journal of Pharmaceutical Science and Research. 2017; 9(5): 680-684.

  • Nasyanka AL. Hubungan Kuantitatif Struktur Aktivitas Sitotoksik Dari Senyawa Induk N-Benzoil-N’-(4-flurorfenil)tiourea dan Turunannya Terhadap Sel Line MCF-7, Tesis, Surabaya : Fakultas Farmasi Universitas Airlangga. 2017.

  • Zhao, S., Ohara, S., Kanno, Y., Midorikawa, Y., Nakayama, M., Makimura, M., and Inouye, Y. HER2 overexpression-mediated inflammatory signaling enhances mammosphere formation through up-regulation of aryl hydrocarbon receptor transcription. Cancer letters., 2013; 330(1): 41-48.

  • Widiandani T, Siswandono, Meiyanto E., Purwanto, BT., Sulistyowati, MI., Hardjono S. New N-Allylthiourea derivatives: Synthesis, molecular docking and in vitro cytotoxicity studies. Tropical Journal of Pharmaceutical Research. 2018;17(8): 1607-1613

  • Widiandani L, Arifianti L, Siswandono. Docking, Synthesis and Cytotoxicity Test on Human Breast Cancer Cell Line (t47d) of N-Allylcarbamothioyl) Benzamide. International Journal of Pharmaceutical and Clinical Research. 2016; 8(5): 372-37

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del Rev. 2001;46(1-3): 3-26.

  • Pires, D.E., Blundell, T.L. and Ascher, D.B., pkCSM: Predicting Smallmolecule Pharmacokinetic and Toxicity Properties using Graph-based Signatures, J. Med. Chem. 2015; 58(9): 4066-4072. DOI:10.1021/acs.jmedchem.5b00104.


Abstract Views: 194

PDF Views: 0




  • Molecular Docking of N-benzoyl-N'-(4-fluorophenyl) thiourea Derivatives as Anticancer Drug Candidate and Their ADMET Prediction

Abstract Views: 194  |  PDF Views: 0

Authors

Suko Hardjono
Department of Pharmaceutical Chemistry, Universitas Airlangga, Surabaya 60286, Indonesia
Tri Widiandani
Department of Pharmaceutical Chemistry, Universitas Airlangga, Surabaya 60286, Indonesia
Bambang T. Purwanto
Department of Pharmaceutical Chemistry, Universitas Airlangga, Surabaya 60286, Indonesia
Anindi L. Nasyanka
Delima Persada School of Health Sciences, Gresik, Indonesia

Abstract


The pharmacophore group found in N-benzoyl-N’-(4-fluorophenyl) thiourea is the same as the urea derivative which has anti-cancer activity, such as hydroxyurea. Because of the presence of these pharmacophore groups, this compound is worthy of being used as parent compound for further development through structural modification. Structural modification as an effort to design the new drug is done by changing the substituted group, which will cause changes in physicochemical properties. The change in physicochemical properties can affect the pharmacokinetics process, toxicity and activity of each compound that can be predicted through molecular modeling. The aims of this present study are to obtain the N-benzoyl-N'-(4-fluorophenyl) thiourea derivatives which is predicted to have the best anticancer activity and is not toxic based on the in silico approach. One of the mechanism of action of the N-benzoil- N'-(4-fluorophenyl) thiourea derivative as an anti-cancer is to inhibit the Sirtuin1 enzyme (SIRT1). The inhibition of the enzyme causes over expression of p53 which is the gene responsible for negative regulation of the cell cycle by using the Chem Bio Draw Ultra 13.0 program which can predict physico-chemical properties of Log P, MR and Etot. Pharmacokinetic properties (ADME) and toxicity were determined using the online pkCSM program. The in silico test is carried out by documenting compounds which will be predicted by the target enzyme SIRT1 with PDB ID: 4I5I. Documentation results in the form of bond energy which is illustrated by the value of the Rerank Score (RS), using the MVD program (Molegro Virtual Docker). Compounds that have small RS values are predicted to have a large activity. From the results of the in silico test using the MVD program and the online pkCSM program it can be seen that 4 (four) N-benzoyl-N'-(4-fluorophenyl)thiourea derivatives are predicted to have good pharmacokinetics (ADME) properties, causing relatively low toxicity except N-4-trifluoromethyl-benzoyl-N’-(4-fluorophenyl)thiourea which can cause hepatotoxics. All compounds have cytotoxic activity greater than the comparative ligand 4I5_601. Compounds of N-4-chlorobenzoyl-N'-(4-fluorophenyl) thiourea are compounds that are predicted to have the most activity and are not toxic.

Keywords


Molecular Modeling, N-Benzoyl-N’-(4-Fluorophenyl) Thiourea, Physico-Chemistry, ADME Prediction.

References