Abstract
Monoacylglycerol lipase (MGL) is primarily responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), an endocannabinoid with full agonist activity at both cannabinoid receptors. Increased tissue 2-AG levels consequent to MGL inhibition are considered therapeutic against pain, inflammation, and neurodegenerative disorders. However, the lack of MGL structural information has hindered the development of MGL-selective inhibitors. Here, we detail a fully refined homology model of MGL which preferentially identifies MGL inhibitors over druglike noninhibitors. We include for the first time insight into the active-site geometry and potential hydrogen-bonding interactions along with molecular dynamics simulations describing the opening and closing of the MGL helical-domain lid. Docked poses of both the natural substrate and known inhibitors are detailed. A comparison of the MGL active-site to that of the other principal endocannabinoid metabolizing enzyme, fatty acid amide hydrolase, demonstrates key differences which provide crucial insight toward the design of selective MGL inhibitors as potential drugs.
Similar content being viewed by others
References
Blankman JL, Simon GM, Cravatt BF (2007) Chem Biol 14:1347
Ghafouri N, Tiger G, Razdan RK, Mahadevan A, Pertwee RG, Martin BR, Fowler CJ (2004) Br J Pharmacol 143:774
Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D (2002) Proc Natl Acad Sci USA 99:10819
Dinh TP, Kathuria S, Piomelli D (2004) Mol Pharmacol 66:1260
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Nature 384:83
Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (2002) Science 298:1793
Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Proc Natl Acad Sci USA 98:9371
Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH (2004) Proc Natl Acad Sci USA 101:10821
Romero FA, Du W, Hwang I, Rayl TJ, Kimball FS, Leung D, Hoover HS, Apodaca RL, Breitenbucher JG, Cravatt BF, Boger DL (2007) J Med Chem 50:1058
Mor M, Rivara S, Lodola A, Plazzi PV, Tarzia G, Duranti A, Tontini A, Piersanti G, Kathuria S, Piomelli D (2004) J Med Chem 47:4998
Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent RA, Nomanbhoy TK, Alexander JP, Cravatt BF (2007) Biochemistry 46:13019
Ollis DL, Cheah E, Cygler M, Dijkstra B, Frolow F, Franken SM, Harel M, Remington SJ, Silman I, Schrag J, Sussman JL, Verschueren KHG, Goldman A (1992) Protein Eng 5:197
Viso A, Cisneros JA, Ortega-Gutierrez S (2008) Curr Top Med Chem 8:231
Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C (1997) J Biol Chem 272:27218
Saario SM, Poso A, Juvonen RO, Jarvinen T, Salo-Ahen OMH (2006) J Med Chem 49:4650
Gonsiorek W, Lunn C, Fan XD, Narula S, Lundell D, Hipkin RW (2000) Mol Pharmacol 57:1045
Hillard CJ (2000) Prostaglandins Other Lipid Mediat 61:3
Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B (2007) Br J Pharmacol 152:787
Hohmann AG (2007) Br J Pharmacol 150:673
Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) Nature 435:1108
Saario SM, Laitinen JT (2007) Basic Clin Pharmacol Toxicol 101:287
Zvonok N, Williams J, Johnston M, Panarinathan L, Janero DR, Li J, Krishnan SC, Makriyannis A (2008) J Proteome Res 7:2158
Zvonok N, Williams J, Johnston M, Panarinathan L, Karageorgos I, Janero DR, Krishnan SC, Makriyannis A (2008) Chem Biol 15:854
Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF (2009) Nat Chem Biol 5:37
Ortar G, Cascio MG, Moriello AS, Camalli M, Morera E, Nalli M, Di Marzo V (2008) Eur J Med Chem 43:62
Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L, Simmons RMA, Li D, Iyengar S, Felder CC (2005) Proc Natl Acad Sci USA 102:17852
Alexander JP, Cravatt BF (2006) J Am Chem Soc 128:9699
Makara JK, Mor M, Fegley D, Szabo SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D (2005) Nat Neurosci 8:1139
Saario SM, Laitinen JT (2007) Chem Biodivers 4:1903
Vandevoorde S, Jonsson KO, Labar G, Persson E, Lambert DM, Fowler CJ (2007) Br J Pharmacol 150:186
King AR, Duranti A, Tontini A, Rivara S, Rosengarth A, Clapper JR, Astarita G, Geaga JA, Luecke H, Mor M, Tarzia G, Piomelli D (2007) Chem Biol 14:1357
Kaneko T, Tanaka N, Kumasaka T (2005) Protein Sci 14:558
Prime version 1.6 (2007) Schrödinger. LLC, New York
Jones DT (1999) J Mol Biol 292:195
Berendsen HJC, Postma JPM, Vangunsteren WF, Dinola A, Haak JR (1984) J Chem Phys 81:3684
Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089
Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) J Chem Phys 103:8577
Hess B, Bekker H, Berendsen HJC, Fraaije J (1997) J Comput Chem 18:1463
van Gunsteren WF, Billeter SR, Eising AA, Hünenberger PH, Krüger P, Mark AE, Scott WRP, Tironi IG (1996) Biomolecular simulation: the GROMOS96 manual and user guide. vdf Hochschulverlag AG, Zürich
Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) In: Pullman B (ed) Intermolecular forces. Reidel, Dordrecht, pp 331–342
Berendsen HJC, Vanderspoel D, Vandrunen R (1995) Comput Phys Commun 91:43
Lindahl E, Hess B, van der Spoel D (2001) J Mol Model 7:306
MacroModel XCluster version 9.5 (2005) Schrödinger. LLC, New York
Shenkin PS, McDonald DQ (1994) J Comput Chem 15:899
Barrett CP, Hall BA, Noble MEM (2004) Acta Crystallogr D Biol Crystallogr 60:2280
Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33
LigPrep version 2.2 (2005) Schrödinger. LLC, New York
Glide version 5.0 (2008) Schrödinger. LLC, New York
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) J Med Chem 47:1739
Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) J Med Chem 47:1750
Goparaju SK, Ueda N, Yamaguchi H, Yamamoto S (1998) FEBS Lett 422:69
Muccioli GG, Labar G, Lambert DM (2008) Chembiochem 9:2704
Ortar G, Bisogno T, Ligresti A, Morera E, Nalli M, Di Marzo V (2008) J Med Chem 51:6970
Cisneros JA, Vandevoorde S, Ortega-Gutierrez S, Paris C, Fowler CJ, Lopez-Rodriguez ML (2007) J Med Chem 50:5012
Kapanda CN, Muccioli GG, Labar G, Draoui N, Lambert DM, Poupaert JH (2009) Med Chem Res 18:243
Saario SM, Savinainen JR, Laitinen JT, Jarvinen T, Niemi R (2004) Biochem Pharmacol 67:1381
Charifson PS, Corkery JJ, Murcko MA, Walters WP (1999) J Med Chem 42:5100
Vandevoorde S (2008) Curr Top Med Chem 8:247
Petrek M, Otyepka M, Banas P, Kosinova P, Koca J, Damborsky J (2006) BMC Bioinformatics 7:316
Acknowledgments
This work has been supported by grants from the National Institutes of Health, National Institutes on Drug Abuse: DA3801, DA07312 and DA000493. We thank Ioannis Karageorgos and Drs. Nikolai Zvonok, Lakshmipathi Pandarinathan, and David Janero for useful discussions.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Bowman, A.L., Makriyannis, A. Refined homology model of monoacylglycerol lipase: toward a selective inhibitor. J Comput Aided Mol Des 23, 799–806 (2009). https://doi.org/10.1007/s10822-009-9289-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10822-009-9289-9