Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor

Abstract

The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a with IC50 value and the selectivity for COX-2 0.6 nM and 1666, respectively. The MTD of (S)-3a was 2000 mg kg−1 and its pharmacokinetic studies in rat showed t1/2 7.5 h. This compound reversed acetic acid induced analgesia and carragennan induced inflammation by 50% and 25% in rat when used at a dose 10 mg kg−1. Mechanistically, it was found that compound (S)-3a inhibits COX-2. Overall, the combination of physico-chemical and biological experiments facilitated the development of a new lead molecule to anti-inflammatory drug.

Bergapten Ameliorates Vincristine-Induced Peripheral Neuropathy by Inhibition of Inflammatory Cytokines and NFκB Signaling

“…The 3D crystal structures of COX-2 (PDB ID 1CVU), iNOS (PDB ID 3E7G), and NF-kB (PDB ID 1NFK) were downloaded from the Protein Data Bank (www.rcsb.org) and used for the docking studies. Bergapten was docked in the active sites of enzymes by using the Schrodinger (Schrodinger Release 2015-4: Maestro, version 10.0, Schrodinger, LLC, New York, NY, 2014) 55 software package and following the protein preparation, ligand preparation, receptor grid generation steps for docking. The most active bergapten shows the highest docking score, hydrogen bonding of its carbonyl group, and π−π interaction of its hydrophobic residue with amino acid residue inside the active site of enzymes.…”

Gadolinium-Based Neuroprognostic Magnetic Resonance Imaging Agents Suppress COX-2 for Prevention of Reperfusion Injury after Stroke

“…Incremental additions of COX-2 to neuroprognostic agent solutions result in concomitant decreases in absorbance, indicating an interaction between the neuroprognostic agent and COX-2 because of π−π and hydrophobic interactions. 33 Binding constants are determined using the Benesi−Hildebrand equation (eq 3). 34 COX-2 binding affinities (K a ) of Gd-DO3A-Dif and Gd-DO3A-Sul are 16.76 × 10 6 M and 13.66 × 10 6 M, respectively, and are higher than those of traditional NSAIDs (Figure 3C,D).…”

“…UV–vis spectrophotometry was performed to confirm the direct COX-2 binding properties of the neuroprognostic agents. Incremental additions of COX-2 to neuroprognostic agent solutions result in concomitant decreases in absorbance, indicating an interaction between the neuroprognostic agent and COX-2 because of π–π and hydrophobic interactions . Binding constants are determined using the Benesi–Hildebrand equation (eq ).…”

In silico and in vitro anti-inflammatory study of phenolic compounds isolated from Eucalyptus maculata resin

“…Based on the previous promising in vitro biological evaluation results, compounds (C1, C2, C4, and C5) isolated from MCF were selected for molecular docking studies into the binding site of COX-2 enzyme to develop an insight into the putative intermolecular interactions and explore the possible binding pattern behind the inhibitory activities of these compounds. The choice of COX-2 for performing the docking study was mainly because it is a vital key enzyme in inflammation and is considered a rate-limiting enzyme that catalyzes prostaglandin production, responsible for the formation of inflammatory mediators [24][25][26][27][28] . The docking study was performed using Molecular Operating Environment software (MOE, 2016.0802).…”