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Structural Insight into Binding Mode of 9-Hydroxy Aristolochic Acid, Diclofenac and Indomethacin to PLA2

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Abstract

Phospholipase A2 (PLA2) catalyzes the hydrolysis of phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is modified by cyclooxygenases into active compounds called eicosanoids that act as signaling molecules in a number of physiological processes. Excessive production of eicosanoids leads to several pathological conditions such as inflammation. In order to block the inflammatory effect of these compounds, upstream enzymes such as PLA2 are valid targets. In the present contribution, molecular dynamic analysis was performed to evaluate the binding of diclofenac, 9-hydroxy aristolochic acid (9-HAA) and indomethacin to PLA2. Obtained results revealed that 9-HAA could form a more stable complex with PLA2 when compared to diclofenac and indomethacin. Furthermore, analysis of intermolecular binding energy components indicated that hydrophobic interactions were dominant in binding process. On the basis of obtained data, inhibitors bearing fused rings with hydrogen acceptor/donor substituent(s) interacted with His48 and Asp49 residues of the active site. More affinity toward PLA2 might be envisaged through negatively charged moieties via interaction with Trp31, Lys34 and Lys69.

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Acknowledgments

Financial supports of this project by Hamadan University of Medical Sciences are acknowledged. We are also grateful for the support of the Ardabil University of Medical Sciences.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran

    Mohsen Ebrahimi

  2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Omidreza Firuzi & Ramin Miri

  3. Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Nima Razzaghi-Asl

  4. Drugs and Advanced Sciences Research Center, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Nima Razzaghi-Asl

  5. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

    Ahmad Ebadi

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  1. Mohsen Ebrahimi
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Correspondence to Nima Razzaghi-Asl or Ahmad Ebadi.

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Ebrahimi, M., Firuzi, O., Miri, R. et al. Structural Insight into Binding Mode of 9-Hydroxy Aristolochic Acid, Diclofenac and Indomethacin to PLA2 . Interdiscip Sci Comput Life Sci 10, 400–410 (2018). https://doi.org/10.1007/s12539-016-0197-0

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  • DOI: https://doi.org/10.1007/s12539-016-0197-0

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