ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

Binding Conformation of 2-Oxoamide Inhibitors to Group IVA Cytosolic Phospholipase A2 Determined by Molecular Docking Combined with Molecular Dynamics

View Author Information
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
Chemical Laboratories, Agricultural University of Athens, Athens, Greece
§ Department of Chemistry and Biochemistry and Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0601, United States
*Tel. (+30210) 7274462 (G.K.), (+30210) 7274475 (T.M.). E-mail: [email protected], [email protected]
Cite this: J. Chem. Inf. Model. 2012, 52, 1, 243–254
Publication Date (Web):December 24, 2011
Copyright © 2011 American Chemical Society

    Article Views





    Read OnlinePDF (4 MB)
    Supporting Info (1)»


    Abstract Image

    The group IVA cytosolic phospholipase A2 (GIVA cPLA2) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA2 inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA2 active site through a combination of molecular docking calculations and molecular dynamics simulations. Recently, the location of the 2-oxoamide inhibitor AX007 within the active site of the GIVA cPLA2 was determined using a combination of deuterium exchange mass spectrometry followed by molecular dynamics simulations. After the optimization of the AX007-GIVA cPLA2 complex using the docking algorithm Surflex-Dock, a series of additional 2-oxoamide inhibitors have been docked in the enzyme active site. The calculated binding affinity presents a good statistical correlation with the experimental inhibitory activity (r2 = 0.76, N = 11). A molecular dynamics simulation of the docking complex of the most active compound has revealed persistent interactions of the inhibitor with the enzyme active site and proves the stability of the docking complex and the validity of the binding suggested by the docking calculations. The combination of molecular docking calculations and molecular dynamics simulations is useful in defining the binding of small-molecule inhibitors and provides a valuable tool for the design of new compounds with improved inhibitory activity against GIVA cPLA2.

    Supporting Information

    Jump To

    Data and discussion for the interactions of 2-oxoamide inhibitors. This material is available free of charge via the Internet at

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 20 publications.

    1. Varnavas D. Mouchlis, Edward A. Dennis. Membrane Association Allosterically Regulates Phospholipase A2 Enzymes and Their Specificity. Accounts of Chemical Research 2022, 55 (23) , 3303-3311.
    2. Yuan-Hao Hsu, Denis Bucher, Jian Cao, Sheng Li, Sheng-Wei Yang, George Kokotos, Virgil L. Woods, Jr, J. Andrew McCammon, and Edward A. Dennis . Fluoroketone Inhibition of Ca2+-Independent Phospholipase A2 through Binding Pocket Association Defined by Hydrogen/Deuterium Exchange and Molecular Dynamics. Journal of the American Chemical Society 2013, 135 (4) , 1330-1337.
    3. Varnavas D. Mouchlis, Georgia Melagraki, Thomas Mavromoustakos, George Kollias, and Antreas Afantitis . Molecular Modeling on Pyrimidine-Urea Inhibitors of TNF-α Production: An Integrated Approach Using a Combination of Molecular Docking, Classification Techniques, and 3D-QSAR CoMSIA. Journal of Chemical Information and Modeling 2012, 52 (3) , 711-723.
    4. Shibbir Ahmed Khan, Marc A. Ilies. Phospholipases A2. 2024, 101-136.
    5. Kshipra S. Karnik, Aniket P. Sarkate, Aishwarya P. Rajhans, Pravin S. Wakte. Assessment of Binding Site and Development of Small Molecule Inhibitors Targeting Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer (NSCLC). Letters in Drug Design & Discovery 2023, 20 (9) , 1204-1218.
    6. Prisilla Arockiasamy, Sriram Srinivasan, Madhanraj Akilandeswari Pugalendhi, Savariyar Josephinol, Kumar Kalavthi Murugan. Analyzing the interaction of synthetic inhibitors with phospholipases through in silico methods. 2023, 243-254.
    7. Feng Geng, Guangxu Zhang, Yadi Wang, Junhong Lü. Membrane phosphatidylserine allosterically regulates the cytosolic phospholipase A2 activity via an electrostatic-switch mechanism. Soft Matter 2022, 18 (11) , 2203-2210.
    8. Kshipra S. Karnik, Aniket P. Sarkate, Deepak K. Lokwani, Ishudeep S. Narula, Prasad V. L. S. Burra, Pravin S. Wakte. Development of triple mutant T790M/C797S allosteric EGFR inhibitors: a computational approach. Journal of Biomolecular Structure and Dynamics 2021, 39 (15) , 5376-5398.
    9. Sang-Chul Kim, Xuemin Wang. Lipids | Phospholipase A in Animals and Plants. 2021, 744-757.
    10. Ching-Yi Cheng, Ashanul Haque, Ming-Fa Hsieh, Syed Imran Hassan, Md. Serajul Haque Faizi, Necmi Dege, Muhammad S. Khan. 1,4-Disubstituted 1H-1,2,3-Triazoles for Renal Diseases: Studies of Viability, Anti-Inflammatory, and Antioxidant Activities. International Journal of Molecular Sciences 2020, 21 (11) , 3823.
    11. Aikaterini Nikolaou, Maroula G. Kokotou, Sofia Vasilakaki, George Kokotos. Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2019, 1864 (6) , 941-956.
    12. Varnavas D. Mouchlis, Edward A. Dennis. Phospholipase A2 catalysis and lipid mediator lipidomics. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2019, 1864 (6) , 766-771.
    13. David Stanley, Yonggyun Kim. Insect prostaglandins and other eicosanoids: From molecular to physiological actions. 2019, 283-343.
    14. Alexis M. Vasquez, Varnavas D. Mouchlis, Edward A. Dennis. Review of four major distinct types of human phospholipase A2. Advances in Biological Regulation 2018, 67 , 212-218.
    15. Cheng Yang Ng, Srinivasaraghavan Kannan, Yong Jun Chen, Francis Chee Kuan Tan, Wee Yong Ong, Mei Lin Go, Chandra S. Verma, Chian-Ming Low, Yulin Lam. A New Generation of Arachidonic Acid Analogues as Potential Neurological Agent Targeting Cytosolic Phospholipase A2. Scientific Reports 2017, 7 (1)
    16. Hui Wang, Michael G. Klein, Gyorgy Snell, Weston Lane, Hua Zou, Irena Levin, Ke Li, Bi-Ching Sang. Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition. Journal of Molecular Biology 2016, 428 (13) , 2769-2779.
    17. Varnavas D. Mouchlis, Edward A. Dennis. Membrane and inhibitor interactions of intracellular phospholipases A2. Advances in Biological Regulation 2016, 61 , 17-24.
    18. Varnavas D. Mouchlis, Denis Bucher, J. Andrew McCammon, Edward A. Dennis. Membranes serve as allosteric activators of phospholipase A 2 , enabling it to extract, bind, and hydrolyze phospholipid substrates. Proceedings of the National Academy of Sciences 2015, 112 (6)
    19. Victoria Magrioti, George Kokotos. Phospholipase A 2 inhibitors for the treatment of inflammatory diseases: a patent review (2010 – present). Expert Opinion on Therapeutic Patents 2013, 23 (3) , 333-344.
    20. Xiaolin Li, Li Ye, Xiaoxiang Wang, Xinzhou Wang, Hongling Liu, Xiangping Qian, Yongliang Zhu, Hongxia Yu. Molecular docking, molecular dynamics simulation, and structure-based 3D-QSAR studies on estrogenic activity of hydroxylated polychlorinated biphenyls. Science of The Total Environment 2012, 441 , 230-238.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect