Insights into cyclooxygenase-2 inhibition by isolated bioactive compounds 3-caffeoyl-4-dihydrocaffeoyl quinic acid and isorhamnetin 3-O-β-D-glucopyranoside from Salicornia herbacea

Ashutosh Bahuguna; Shiv Bharadwaj; Vivek K Bajpai; Shruti Shukla; Dong Wook Won; InWha Park; MinKyun Na; Sonam Sonwal; Yun Suk Huh; Young-Kyu Han; Jesus Simal-Gandara; Jianbo Xiao; Myunghee Kim

doi:10.1016/j.phymed.2021.153638

Insights into cyclooxygenase-2 inhibition by isolated bioactive compounds 3-caffeoyl-4-dihydrocaffeoyl quinic acid and isorhamnetin 3-O-β-D-glucopyranoside from Salicornia herbacea

Phytomedicine. 2021 Sep:90:153638. doi: 10.1016/j.phymed.2021.153638. Epub 2021 Jun 29.

Authors

Ashutosh Bahuguna¹, Shiv Bharadwaj², Vivek K Bajpai³, Shruti Shukla⁴, Dong Wook Won⁵, InWha Park⁶, MinKyun Na⁷, Sonam Sonwal⁸, Yun Suk Huh⁹, Young-Kyu Han¹⁰, Jesus Simal-Gandara¹¹, Jianbo Xiao¹², Myunghee Kim¹³

Affiliations

¹ Department of Food Science and Technology, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 38541, South Korea.
² Nanotechnology Research and Application Center, Sabanci University, Istanbul 34956, Turkey.
³ Department of Energy and Materials Engineering, Dongguk University, Seoul 04620, South Korea.
⁴ TERI-Deakin Nanobiotechnology Centre, The Energy and Resources Institute, Gwal Pahari, Gurugram, Haryana 122003, India.
⁵ College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.
⁶ Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung, Gangwon-do 25451, South Korea.
⁷ College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea. Electronic address: mkna@cnu.ac.kr.
⁸ Department of Biological Engineering, Biohybrid Systems Research Center (BSRC), Inha University, Incheon 22212, South Korea.
⁹ Department of Biological Engineering, Biohybrid Systems Research Center (BSRC), Inha University, Incheon 22212, South Korea. Electronic address: yunsuk.huh@inha.ac.kr.
¹⁰ Department of Energy and Materials Engineering, Dongguk University, Seoul 04620, South Korea. Electronic address: ykenergy@dongguk.edu.
¹¹ Department of Analytical Chemistry and Food Science, University of Vigo - Ourense Campus, E-32004 Ourense, Spain.
¹² Department of Analytical Chemistry and Food Science, University of Vigo - Ourense Campus, E-32004 Ourense, Spain; International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China. Electronic address: jianboxiao@yahoo.com.
¹³ Department of Food Science and Technology, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 38541, South Korea. Electronic address: foodtech@ynu.ac.kr.

PMID: 34275700
DOI: 10.1016/j.phymed.2021.153638

Abstract

Background: Cyclooxygenase-2 (COX-2) is an important enzyme with numerous biological functions. Overexpression of COX-2 has been associated with various inflammatory-related diseases and therefore, projected as an important pharmacological target.

Purpose: We aimed to investigate the inhibitory potential of isolated bioactive compounds, 3-caffeoyl-4-dihydrocaffeoyl quinic acid (CDQ) and isorhamnetin 3-O-β-d-glucopyranoside (IDG), from Salicornia herbacea against COX-2 using both computational and in vitro approaches.

Methods: Computational analysis, including molecular docking, molecular dynamics (MD) simulations, and post-simulations analysis, were employed to estimate the binding affinity and stability of CDQ and IDG in the catalytic pocket of COX-2 against Celecoxib as positive control. These predictions were further evaluated using in vitro enzyme inhibition as well as gene expression mediation in macrophages cells.

Results: Molecular docking analysis revealed substantial binding energy of CDQ (-6.1 kcal/mol) and IDG (-5.9 kcal/mol) with COX-2, which are lower than Celecoxib (-8.1 kcal/mol). MD simulations (100 ns) and post simulation analysis exhibited the substantial stability and binding affinity of docked CDQ and IDG compounds with COX-2. In vitro assays indicated significant COX-2 inhibition by CDQ (IC₅₀ = 76.91 ± 2.33 μM) and IDG (IC₅₀ = 126.06 ± 9.44 μM). This result supported the inhibitory potential of isolated bioactive compounds against COX-2. Also, a cellular level study revealed a downregulation of COX-2 expression in tumor necrosis factor-alpha stimulated RAW 264.7 macrophages treated with CDQ and IDG.

Conclusion: Computational and experimental analysis of CDQ and IDG from S. herbacea established their potential in the inhibition and mediation of COX-2. Hence, CDQ and IDG can be considered for therapeutic development against COX-2 linked disorders, such as inflammation and cancer. Furthermore, CDQ and IDG structures can be served as a lead compound for the development of advanced novel anti-inflammatory drugs.

Keywords: Cyclooxygenase-2; Enzyme inhibition; Inflammation; Molecular docking; Salicornia herbacea.

MeSH terms

Animals
Chenopodiaceae* / chemistry
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors* / pharmacology
Mice
Molecular Docking Simulation
Molecular Structure
Quercetin / analogs & derivatives*
Quercetin / pharmacology
Quinic Acid* / pharmacology
RAW 264.7 Cells
Structure-Activity Relationship

Substances

Cyclooxygenase 2 Inhibitors
Quinic Acid
3-methylquercetin
Quercetin
Cyclooxygenase 2