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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
     

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

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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