title: Structural Insight into Binding Mode of 9-Hydroxy Aristolochic Acid, Diclofenac and Indomethacin to PLA2.
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 PLA2are 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 PLA2when 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 PLA2might be envisaged through negatively charged moieties via interaction with Trp31, Lys34 and Lys69.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ebrahimi
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Omidreza
authors.initials: O
authors.lastname: Firuzi
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran. n.razzaghi@pharmacy.arums.ac.ir.|Drugs and Advanced Sciences Research Center, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran. n.razzaghi@pharmacy.arums.ac.ir.
authors.forename: Nima
authors.initials: N
authors.lastname: Razzaghi-Asl
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran. a.ebadi@umsha.ac.ir.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Ebadi
mesh_terms: D034341:Aristolochic Acids / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004008:Diclofenac / Q000737:chemistry* / Q000378:metabolism*; D007213:Indomethacin / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D054467:Phospholipases A2 / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity
chemical_list: C505883:9-hydroxy aristolochic acid I; D034341:Aristolochic Acids; D008024:Ligands; D004008:Diclofenac; D054467:Phospholipases A2; D007213:Indomethacin
keywords: In silico drug design; Inflammation; Molecular dynamic simulation; Phospholipase A2