Drug discovery is a lengthy and costly process which aims at bringing in a novel therapeutic molecule for the treatment of various diseases. In the present study, a novel series of eighty chalcone derivatives [(4-substituted)-(4'-substituted)-3' substituted sulphonyl (2E)-1,3-diphenylprop-2-en-1-one] were designed to inhibit soluble epoxide hydrolase enzyme (sEH). Lipinski's rule of 5 and absorption, distribution, metabolism, elimination and toxicity (ADMET) properties of the compounds were calculated using Molinspiration server and Accord for excel software respectively. All 80 compounds have passed the Lipinski's rule of 5 and only 20 compounds showed considerable ADMET properties. These 20 compounds were subjected to molecular docking studies using AutoDock 4.2 in order to rationalize the possible interactions between test compounds and the active site of human soluble epoxide hydrolase enzyme (1ZD3). Binding energy, intermolecular energy and inhibition constant were the main parameters taken into consideration in this study. The binding energies ranged from -6.07 to -7.89 kcal/mol, the inhibition constant ranging from 1.64 µM to 35.45 µM and intermolecular energy ranging between -9.38 kcal/mol to -6.97 kcal/mol. Hence, further pharmacophore optimization and in vivo studies are necessary to develop potent chemical entities that could inhibit the sEH enzyme.
Objective Soluble epoxide hydrolase (sEH) belongs to the α/β -hydrolase superfamily, a subclass of α/β proteins. Chalcones are chemical compounds that show hopeful obliging efficacy in controlling numerous diseases. The main objective of the study is to evaluate the sEH inhibitory activity of some synthesized chalcone derivatives and identification of its mode of inhibition. Methods Four different chalcone derivatives (PC-1 to PC-4) were selected for synthesis by Claisen-Schmidt method. The in vitro sEH inhibitory activity was performed for the synthesized compounds by fluorimetric assay. The percentage of sEH activity and IC50 values were calculated for the synthesized compounds. Dissociation constant were determined by following the method described by Lineweaver-Burks plot. Results and Conclusions The IC50 value obtained for PC-1, PC-2, PC-3, and PC-4 were found to be 0.8213 µg/mL, 2.64 µg/mL, 0.2490 µg/mL and 0.5238 µg/mL respectively. The order of potency (IC50) of the chalcone and chalcone oxide in sEH inhibition assay was PC-3 > PC-4 > PC-1 >PC-2. All the compounds (PC-1, PC-2, PC-3) showed mixed type of inhibition except PC-4 which showed non-competitive type of inhibition. Further in vivo studies are to be carried out for these compounds to confirm their activity and explore the mechanism by which these compounds act and rationalize their use.
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