Evaluation of Selective COX-2 Inhibition and In Silico Study of Kuwanon Derivatives Isolated from Morus alba

Abstract

Six kuwanon derivatives (A/B/C/E/H/J) extracted from the roots of Morus alba L. were evaluated to determine their cyclooxygenase (COX)-1 and 2 inhibitory effects. Cyclooxygenase (COX) is known as the target enzyme of nonsteroidal anti-inflammatory drugs (NSAIDs), which are the most widely used therapeutic agents for pain and inflammation. Among six kuwanon derivatives, kuwanon A showed selective COX-2 inhibitory activity, almost equivalent to that of celecoxib, a known COX inhibitor. Kuwanon A showed high COX-2 inhibitory activity (IC50 = 14 μM) and a selectivity index (SI) range of >7.1, comparable to celecoxib (SI > 6.3). To understand the mechanisms underlying this effect, we performed docking simulations, fragment molecular orbital (FMO) calculations, and pair interaction energy decomposition analysis (PIEDA) at the quantum-mechanical level. As a result, kuwanon A had the strongest interaction with Arg120 and Tyr355 at the gate of the COX active site (−7.044 kcal/mol) and with Val89 in the membrane-binding domain (−6.599 kcal/mol). In addition, kuwanon A closely bound to Val89, His90, and Ser119, which are residues at the entrance and exit routes of the COX active site (4.329 Å). FMO calculations and PIEDA well supported the COX-2 selective inhibitory action of kuwanon A. It showed that the simulation and modeling results and experimental evidence were consistent.

Exploring potential antidiabetic and anti-inflammatory flavonoids from Euphorbia humifusa with an integrated strategy

“…Nonetheless, both of them revealed better BE value than the NSAID indomethacin which were ranked as follows vitexin (−9.19 kcal/mol)> astragalin (−8.94 kcal/mol)> indomethacin (−6.64 kcal/mol). The interactions of those potential ligands with the reported important key residues Arg120, Arg513, Tyr355, and Val523 inside the active pocket are consistent with the intercalation of selective COX-2 inhibitors docking ( Baek et al, 2021 ).…”

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation

“…The presence of the 2-chloro substituent resulted in COX-2 selectivity, probably by interacting with Pro86 and Val89 through hydrophobic and vdW interactions. Val89 is a residue of the membrane binding domain of COX and is shown to confer greater COX-2 inhibitory potency [ 40 ]. We then docked compounds 5b and 5d in the 6COX active site.…”

Morus alba derived Kuwanon‐A combined with 5‐fluorouracil reduce tumor progression via synergistic activation of GADD153 in gastric cancer

“…Nevertheless, Kuwanon‐A (KA) has not been investigated for its anticancer activity yet. Interestingly, KA shows an extremely high COX‐2 inhibition, almost equivalent to celecoxib, which is a conventional COX‐2 inhibitor and has been employed for cancer therapy 30 . It is noteworthy that the genetic alterations of GADD153 play crucial role in the malignant progression of GC 31 .…”

“…Interestingly, KA shows an extremely high COX-2 inhibition, almost equivalent to celecoxib, which is a conventional COX-2 inhibitor and has been employed for cancer therapy. 30 It is noteworthy that the genetic alterations of GADD153 play crucial role in the malignant progression of GC. 31 Therefore, it is pertinent to evaluate the anti-GC ability of KA via effect on GADD153 as an anticancer target.…”