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

Daeui Park,Seung-Hwa Baek,Tamina Park,Yoon-Ju Kwon,Sungbo Hwang,Myounglae Cho

doi:10.3390/ijms22073659

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.

Highlights

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents to manage pain and inflammation
Six natural products were isolated from Mori cortex and identified by comparing high performance liquid chromatography (HPLC) peak profiles (Figure S1) and NMR data (Figures S2 and S3) with literature values: kuwanon A [28,29], kuwanon B [28,29], kuwanon C [28,29,30], kuwanon E [31], kuwanon G [32], and kuwanon H [32]
These results showed that kuwanon A was a potent inhibitor of COX-2 enzymes, even better than celecoxib

Summary

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents to manage pain and inflammation. COX-1, an enzyme in a constitutive form, is expressed in several tissues and is known to play an important role in the synthesis of cytoprotective prostaglandins in the gastrointestinal tract. COX-2, a predominantly induced form of the enzyme, is constitutively expressed in many tissues such as the prostate, endothelium, brain, and renal medulla [2,3]. COX-1 is a housekeeping enzyme that is widely expressed in most tissues, whereas COX-2, mainly expressed at sites of infection, inflammation, and cancer, produces prostanoids which are responsible for disease pathogenesis. The therapeutic anti-inflammatory action of NSAIDs is associated with the inhibition of COX-2; undesired side effects arise from the inhibition of COX-1 [6]. There is a need for research on anti-inflammatory substances having an improved COX-1/2 selectivity index

Methods

Results

Discussion

Conclusion