In Silico Study and ADMET prediction of N-(4-fluorophenylcarbamothioyl) Benzamide Derivatives as Cytotoxic Agents

Abstract

Structure modification is one of the ways to obtain new derivative compounds. This current study presents pharmacophore-based structure modification of active compounds. Pharmacophore groups are found in urea and phenyl carbamothioyl benzamide (PCTB) compounds, with their derivatives sharing similar pharmacophore groups to that of urea. Any structure modification of a compound will alter its physicochemical properties. In turn, this will also modify the pharmacokinetics of a compound as well as its toxicity. Both the pharmacological activity and pharmacokinetic properties of a compound can be predicted using in-silico molecular modeling studies. This research aims to examine the anticancer activities exhibited by PCTB compounds against HeLA cells by inhibiting CheckPointKinase-1 (CHK1) PDB A42_1 enzymes. The physicochemical properties such as LogP, MR and Etotal of PCTB derivative compounds are also determined. Pharmacokinetic properties are predicted using the pKCSM program. From the results of the in-silico study using Molegro Virtual Docker (MVD) version 5.5, Rerank Scores of PCTB derivative compounds were obtained, for which smaller scores predict higher pharmacological activity. PCTB derivative compounds exhibit higher anticancer activity and pharmacokinetic properties compared to Hydroxyurea. All PCTB compounds and derivatives show lower toxicity except for 4-CF3-PCTB, which shows hepatotoxicity. Compared to the original ligand (A42_1), all PCTB compounds and derivatives indicate higher anticancer activity. Among all of them, 4-Cl-PCTB is the best potential candidate anticancer agent due to its strong activity; it displays no toxicity in its pharmacokinetic properties.

Keywords: In silico; PCTB and its derivatives; anticancer prediction, ADMET prediction, physicochemical properties.