Computational Analysis and Biological Activities of Oxyresveratrol Analogues, the Putative Cyclooxygenase-2 Inhibitors

Abstract

Polyphenols are a large family of naturally occurring phytochemicals. Herein, oxyresveratrol was isolated from ethanolic crude extracts of Artocarpus lacucha Buch.-Ham., and chemically modified to derive its lipophilic analogues. Biological screening assays showed their inhibitory potency against cyclooxygenase-2 (COX-2) with very low cytotoxicity to the MRC-5 normal cell lines. At the catalytic site of COX-2, docking protocols with ChemPLP, GoldScore and AutoDock scoring functions were carried out to reveal hydrogen bonding interactions with key polar contacts and hydrophobic pi-interactions. For more accurate binding energetics, COX-2/ligand complexes at the binding region were computed in vacuo and implicit aqueous solvation using M06-2X density functional with 6-31G+(d,p) basis set. Our computational results confirmed that dihydrooxyresveratrol (4) is the putative inhibitor of human COX-2 with the highest inhibitory activity (IC50 of 11.50 ± 1.54 µM) among studied non-fluorinated analogues for further lead optimization. Selective substitution of fluorine provides a stronger binding affinity; however, lowering the cytotoxicity of a fluorinated analogue to a normal cell is challenging. The consensus among biological activities, ChemPLP docking score and the binding energies computed at the quantum mechanical level is obviously helpful for identification of oxyresveratrol analogues as a putative anti-inflammatory agent.

Pharmacophore study, molecular docking and molecular dynamic simulation of virgin coconut oil derivatives as anti-inflammatory agent against COX-2

“…As the growing importance of accurately estimating binding affinities in drug design is unforeseeably gaining interest, leading to quantum mechanical (QM) approaches to become incredibly popular for designing drugs [ 58 ]. It has been discovered that certain computation of QM parameters, such as a dipole moment and atomic charges, can help increase the precision of a docking process [ 58 , 59 ]. According to the theory of Gibbs’s free energy, the higher or more negative the Δ G value energy produced from the bonds between the ligands and the receptors, the more stable are the bonds [ 60 ].…”

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“…Most of the FDA-approved non-steroidal anti-inflammatory drugs (NSAIDs), whether they are Salicylates [2], Anthranilic acid [3], Arylindoic acid [4], and Oxicame [5] (Scheme 1), possess common structural features of an acidic or amine of an aromatic or heterocyclic ring, and an additional center of lipophilicity mostly aromatic. Their mechanisms are nonselective, inhibiting both COX-I and COX-II isoforms [6,7]. Density-functional theory (DFT) is a computational quantum mechanical method widely used in modern medicinal chemistry to suggest the electronic 3D atoms or molecule structures compute the ground state energy in realistic models of bulky molecules and their surfaces [8,9].…”

“…Docking of Anthranilic acid derivatives (compounds[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] …”