Molecular Docking and Competitive Binding Study Discovered Different Binding Modes of Microsomal Prostaglandin E Synthase-1 Inhibitors

Microsomal prostaglandin E synthase-1 (mPGES-1) is a newly recognized therapeutic target for the treatment of inflammation, pain, cancer, atherosclerosis, and stroke. Many mPGES-1 inhibitors have been discovered. However, as the structure of the binding site is not well-characterized, none of these inhibitors was designed based on the mPGES-1 structure, and their inhibition mechanism remains to be fully disclosed. Recently, we built a new structural model of mPGES-1 which was well supported by experimental data. Based on this model, molecular docking and competition experiments were used to investigate the binding modes of four representive mPGES-1 inhibitors. As the inhibitor binding sites predicted by docking overlapped with both the substrate and the cofactor binding sites, mPGES-1 inhibitors might act as dual-site inhibitors. This inhibitory mechanism was further verified by inhibitor-cofactor and inhibitor-substrate competition experiments. To investigate the potency-binding site relationships of mPGES-1 inhibitors, we also carried out molecular docking studies for another series of compounds. The docking results correlated well with the different inhibitory effects observed experimentally. Our data revealed that mPGES-1 inhibitors could bind to the substrate and the cofactor binding sites simultaneously, and this dual-site binding mode improved their potency. Future rational design and optimization of mPGES-1 inhibitors can be carried out based on this binding mechanism.

[1]  J. Mancini,et al.  Microsomal prostaglandin E2 synthase-1 (mPGES-1): a novel anti-inflammatory therapeutic target. , 2008, Journal of medicinal chemistry.

[2]  O. Werz,et al.  Myrtucommulone, a natural acylphloroglucinol, inhibits microsomal prostaglandin E2 synthase‐1 , 2009, British journal of pharmacology.

[3]  P. Jakobsson,et al.  Identification of Key Residues Determining Species Differences in Inhibitor Binding of Microsomal Prostaglandin E Synthase-1* , 2010, The Journal of Biological Chemistry.

[4]  Luhua Lai,et al.  LigBuilder 2: A Practical de Novo Drug Design Approach , 2011, J. Chem. Inf. Model..

[5]  Wolfgang Albrecht,et al.  Licofelone Suppresses Prostaglandin E2 Formation by Interference with the Inducible Microsomal Prostaglandin E2 Synthase-1 , 2008, Journal of Pharmacology and Experimental Therapeutics.

[6]  R. Morgenstern,et al.  A facilitated approach to evaluate the inhibitor mode and potency of compounds targeting microsomal prostaglandin e synthase-1. , 2011, Assay and drug development technologies.

[7]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[8]  B. Samuelsson,et al.  Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Jesper Z. Haeggström,et al.  Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase , 2007, Nature.

[10]  F. J. Luque,et al.  Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. , 2005, Journal of medicinal chemistry.

[11]  Chang-Guo Zhan,et al.  Human Microsomal Prostaglandin E Synthase-1 (mPGES-1) Binding with Inhibitors and the Quantitative Structure-Activity Correlation , 2008, J. Chem. Inf. Model..

[12]  Jilly F. Evans,et al.  Crystal Structure of Inhibitor-Bound Human 5-Lipoxygenase-Activating Protein , 2007, Science.

[13]  Ralf Morgenstern,et al.  Human Microsomal Prostaglandin E Synthase-1 , 2003, Journal of Biological Chemistry.

[14]  Feng Xu,et al.  A new kinetic model for heterogeneous (or spatially confined) enzymatic catalysis : Contributions from the fractal and jamming (overcrowding) effects , 2007 .

[15]  R. Armstrong,et al.  Location of inhibitor binding sites in the human inducible prostaglandin E synthase, MPGES1. , 2011, Biochemistry.

[16]  B. Persson,et al.  Membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG). A widespread protein superfamily. , 2000, American journal of respiratory and critical care medicine.

[17]  Ralf Morgenstern,et al.  Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target , 2007, Pharmacological Reviews.

[18]  Ralf Morgenstern,et al.  Structural basis for induced formation of the inflammatory mediator prostaglandin E2 , 2008, Proceedings of the National Academy of Sciences.

[19]  O. Werz,et al.  The Molecular Pharmacology and In Vivo Activity of 2-(4-Chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a Dual Inhibitor of Microsomal Prostaglandin E2 Synthase-1 and 5-Lipoxygenase , 2010, Journal of Pharmacology and Experimental Therapeutics.

[20]  L. Lai,et al.  Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity. , 2011, The Biochemical journal.

[21]  N. Méthot,et al.  Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886. , 2005, Bioorganic & medicinal chemistry letters.

[22]  Y. Saeki,et al.  Expression of prostaglandin E synthase mRNA is induced in beta-amyloid treated rat astrocytes , 2000, Neuroscience Letters.

[23]  M. Murakami,et al.  Prostaglandin E synthases: Understanding their pathophysiological roles through mouse genetic models. , 2010, Biochimie.

[24]  O. Werz,et al.  Discovery of benzo[g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E(2) synthase-1. , 2009, Bioorganic & medicinal chemistry.

[25]  N. Méthot,et al.  Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[26]  Ralf Morgenstern,et al.  Structural basis for detoxification and oxidative stress protection in membranes. , 2006, Journal of molecular biology.

[27]  Paul Langan,et al.  X-ray structure of the ternary MTX.NADPH complex of the anthrax dihydrofolate reductase: a pharmacophore for dual-site inhibitor design. , 2009, Journal of structural biology.