Flavonoids as dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX): molecular docking and in vitro studies

Abstract

Background Inflammation is known to involve in many pathological processes of different diseases, but the current therapy causes adverse effects. Thus, there is a great interest for the discovery of flavonoids as a valuable alternative to classical analgesic and anti-inflammatory agent with dual-inhibitory action, especially on both COX-2 and 5-LOX which can minimize or overcome this problem. Results In the present work, drug-likeness properties of the synthesized flavonoids via Lipinski’s Rule of Five were predicted using QikProp prior to evaluation of their COX and LOX inhibitory activities using enzyme assays. Subsequently, molecular docking was performed using GLIDE to analyse their binding behaviour. The results showed that all compounds obeyed the Lipinski’s Rule of Five. NPC6 and NPC7 had displayed better selectivity towards COX-2 as compared to Indomethacin with less than 50% inhibition against COX-1. In addition, these compounds also inhibited activity of 5-LOX. Their selectivity to COX-2 was due to the binding to hydrophobic region and extends to lobby region near the entrance of COX binding site forming hydrogen bond with Ser530. Interestingly, these compounds showed a similar binding mode as Zileuton in the active site of 5-LOX and formed hydrogen bond interaction with Ala424. Conclusion NPC6 and NPC7 had potential as dual inhibitor of COX-2 and 5-LOX. The scaffolds of these chemical entities are useful to be as lead compounds for the dual inhibition of COX-2 and 5-LOX.

Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies

“…Moreover, the strong binding affinity could be attributed to the presence of polar residues, namely Arg120, Ser353, Tyr385, Gly526, and Glu524 that enhance the chances of squeezing the molecule into the active site. To sum up, curcumin’s selectivity to COX-2 was primarily due to the binding to the hydrophobic region and extending to the lobby region near the entrance of the COX-2 binding site, thereby forming hydrogen bonds with Ser530 69 . Moreover, the position of the co-crystallized ligand and the three test compounds inside the catalytic site of COX-2 was stabilized by surrounded hydrophobic interactions.…”

“…Ser353, Tyr355, Tyr385, Ser530, Gly526, and Glu524. This encloses the curcumin molecule in a cage-like structure, justifying its COX-1 inhibition and increasing its selectivity 69 . Capsaicin and gingerol displayed less binding energies and interactions with the COX-1 binding site.…”

The medicinal chemistry of Urtica dioica L.: from preliminary evidence to clinical studies supporting its neuroprotective activity

“…Among the studied compounds and following the docking carried out using AutoDock Vina, the authors identified some polyphenols as promising binders [ 45 ]. This aspect was also described by Idris et al in their contribution in which they investigated polyphenols as ligands for 5-LOX and COX-2 [ 46 ]. For example, quercetin, which is present in U. dioica also in its glycosylated forms, was highlighted as a potential interactor of 5-LOX and COX-2 with anti-inflammatory activity [ 47 ].…”

Analgesic and Anti-Inflammatory Effects of 80% Methanol Extract and Solvent Fractions of the Leaves of Vernonia auriculifera Hiern. (Asteraceae)

“…Prostaglandin synthesis is known to be inhibited by flavonoids. 25 As such, the polyphenols that have been reported in the leaves of V. auriculifera might be responsible for the demonstrated anti-inflammatory and analgesic effects. 14 , 26 In the cotton pellet-induced granuloma model, ME, MEF, and AQF inhibited both exudate and granuloma formation at all investigated concentrations.…”