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Anti-inflammatory Molecules: Enzyme Inhibitors

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Bioresources and Bioprocess in Biotechnology

Abstract

Structure/receptor-based drug design, a new approach of drug discovery, has become a fascinating area of drug discovery/development. This rational approach of drug discovery may lead to the production of many drugs, and some products developed based on this approach are presently available in the market. Examples of some of these drugs include saquinavir for the treatment of AIDS, captopril against hypertension, dorzolamide for glaucoma and Zanamivir against influenza. Many molecules are designed based on their structure or receptors and are under different stages of clinical trials. For applying rational approach, we have to first identify the pathway of pathogenesis and the target proteins related to the specific disease. After the identification of the specific protein, the compound which inhibits the target protein may be designed to fit into the binding site of the protein most appropriately. Compounds from natural sources are tested first, taking cues from various kinds of information. Such compounds may form a basic structure which could be appropriated to the binding site of the target protein. This chapter has been devoted to the inhibitors of the enzymes in the arachidonic acid pathway which may serve as anti-inflammatory compounds. Target enzymes of inflammatory pathway include isozymes of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX).

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References

  • Aparna V, Dileep KV, Mandal PK, Karthe P, Sadasivan C, Haridas M (2012) Anti-inflammatory property of n-hexadecanoic acid: structural evidence and kinetic assessment. Chem Biol Drug Des 80:434–439. doi:10.1111/j.1747-0285.2012.01418

    Article  CAS  PubMed  Google Scholar 

  • Ashley NT, Weil ZM, Nelson RJ (2012) Inflammation: mechanisms, costs, and natural variation. Annu Rev Ecol Evol Syst 43:385–406. doi:10.1146/annurev-ecolsys-040212-092530

    Article  Google Scholar 

  • Batt DG (1992) 5-lipoxygenase inhibitors and their anti-inflammatory activities. Prog Med Chem 29:1–63

    Article  CAS  PubMed  Google Scholar 

  • Brash AR (1999) Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem 274:23679–23682. doi:10.1074/jbc.274.34.23679

    Article  CAS  PubMed  Google Scholar 

  • Burke JE, Dennis EA (2009) Phospholipase A2 structure/function, mechanism, and signalling. J Lipid Res 50:S237–S242. doi:10.1194/jlr.R800033-JLR200

    Article  PubMed  PubMed Central  Google Scholar 

  • Cao H, Yu R, Choi Y, Ma ZZ, Zhang H, **ang W, Lee DY, Berman BM, Moudgil KD, Fong HH, van Breemen RB (2010) Discovery of cyclooxygenase inhibitors from medicinal plants used to treat inflammation. Pharmacol Res 61:519–524. doi:10.1016/j.phrs.2010.02

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandra DN, Prasanth GK, Singh N, Kumar S, Jithesh O, Sadasivan C, Sharma S, Singh TP, Haridas M (2011) Identification of a novel and potent inhibitor of phospholipase A2 in a medicinal plant: crystal structure at 1.93 Ã… and surface Plasmon resonance analysis of phospholipase A2 complexed with berberine. Biochim et Biophys Acta (BBA) – Proteins and Proteomics 1814:657–663. doi:10.1016/j.bbapap.2011.03.002

    Article  CAS  Google Scholar 

  • Chandra DN, Preethidan DS, Sabu A, Haridas M, (2015) Traditional fermentation of ayurvedic medicine yields higher proinflammatory enzyme inhibition compared to wine-model product. Front in Life Sci 8(2): 160–164. doi: http://dx.doi.org/10.1080/21553769.2015.1005245

  • Chauret N, Yergey JA, Brideau C, Friesen RW, Mancini J, Riendeau D, Silva J, Styhler A, Trimble LA, Nicoll-Griffith DA, (2001) In vitro metabolism considerations, including activity testing of metabolites, in the discovery and selection of the COX-2 inhibitor etoricoxib (MK-0663). Bioorg Med Chem Lett 11: 1059–1062. doi: http://dx.doi.org/10.1016/S0960-894X(01)00135-4

  • Chi YS, Jong HG, Son KH, Chang HW, Kang SS, Kim HP (2001) Effects of naturally occurring prenylated flavonoids on enzymes metabolizing arachidonic acid: cyclooxygenases and lipoxygenases. Biochem Pharmacol 62:1185–1191

    Article  CAS  PubMed  Google Scholar 

  • Cholbi R, Ferrándiz ML, Terencio MC, De Rosa S, Alcaraz MJ, Payá M (1996) Inhibition of phospholipase A2 activities and some inflammatory responses by the marine product ircinin. Naunyn Schmiedeberg’s Arch Pharmacol 354(5):677–683

    Article  CAS  Google Scholar 

  • Davidson FF, Hajdu J, Dennis EA (1986) 1-stearyl,2-stearoylaminodeoxy phosphatidylcholine, a potent reversible inhibitor of phospholipase A2. Biochem Biophys Res Commun 137:587–592

    Article  CAS  PubMed  Google Scholar 

  • De Haas GH, van Oort MG, Dijkman R, Verger R (1989) Phospholipase A2 inhibitors: monoacyl, monoacylamino-glycero-phosphocholines. Biochem Soc Trans 17:274–276

    Article  PubMed  Google Scholar 

  • Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G (2011) Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 111:6130–6185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeWitt DL (1999) Cox-2-selective inhibitors: the new super aspirins. Mol Pharmacol 55:625–631

    CAS  PubMed  Google Scholar 

  • Dhanjal JK, Sreenidhi AK, Bafna K, Katiyar SP, Goyal S, Grover A, Sundar D (2015) Computational structure-based de novo design of hypothetical inhibitors against the anti-inflammatory target COX-2. PLoS One 10:e0134691. doi:10.1371/journal.pone.0134691

    Article  PubMed  PubMed Central  Google Scholar 

  • Dileep KV, Tintu I, Sadasivan C (2011) Molecular docking studies of curcumin analogs with phospholipase A2. Interdiscip Sci: Comput Life Sci 3:189–197. doi:10.1007/s12539-011-0090-9

    Article  CAS  Google Scholar 

  • Dileep KV, Remya C, Tintu I, Haridas M, Sadasivan C (2013) Interactions of selected indole derivatives with phospholipase A2: in silico and in vitro analysis. J Mol Model 19:1811–1817. doi:10.1007/s00894-012-1741-4

    Article  CAS  PubMed  Google Scholar 

  • Dillard RD, Bach NJ, Draheim SE, Berry DR, Carlson DG, Chirgadze NY, Clawson DK, Hartley LW, Johnson LM, Jones ND, McKinney ER, Mihelich ED, Olkowski JL, Schevitz RW, Smith AC, Snyder DW, Sommers CD, Wery JP (1996) Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides. J Med Chem 39:5119–5136. doi:10.1021/jm960485v

    Article  CAS  PubMed  Google Scholar 

  • Escrig V, Ubeda A, Ferrandiz ML, Darias J, Sanchez JM, Alcaraz MJ, Paya M (1997) Variabilin: a dual inhibitor of human secretory and cytosolic phospholipase A2 with anti-inflammatory activity. J Pharmacol Exp Ther 282:123–131

    CAS  PubMed  Google Scholar 

  • Farooqui AA, Horrocks LA, Farooqui T, (2000) Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurological disorders. Chem Phys Lipids 106: 1–29. doi: http://dx.doi.org/10.1016/S0009-3084(00)00128-6

  • Flower RJ (2003) The development of COX2 inhibitors. Nat Rev Drug Discov 2:179–191. doi:10.1038/nrd1034

    Article  CAS  PubMed  Google Scholar 

  • Furst R, Zundorf I (2014) Plant-derived anti-inflammatory compounds: hopes and disappointments regarding the translation of preclinical knowledge into clinical progress. Mediat Inflamm Article ID 146832, 9 pages. doi:10.1155/2014/146832

  • Garcia-Pastor P, Randazzo A, Gomez-Paloma L, Alcaraz MJ, Paya M (1999) Effects of petrosaspongiolide M, a novel phospholipase A2 inhibitor, on acute and chronic inflammation. J Pharmacol Exp Ther 289:166–172

    CAS  PubMed  Google Scholar 

  • Gelb MH, Jain MK, Berg OG (1994) Inhibition of phospholipase A2. FASEB J 8(12):916–924

    CAS  PubMed  Google Scholar 

  • Habeeb AG, Rao PPN, Knaus EE (2000) Design and syntheses of diarylisoxazoles: novel inhibitors of cyclooxygenase-2 (COX-2) with analgesic-antiinflammatory activity. Drug Dev Res 51(4):273–286. doi:10.1002/ddr.9

    Article  CAS  Google Scholar 

  • Habeeb AG, Rao PPN, Knaus EE (2001) Design and synthesis of 4,5-Diphenyl-4-isoxazolines: novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity. J Med Chem 44(18):2921–2927. doi:10.1021/jm0101287

    Article  CAS  PubMed  Google Scholar 

  • Hansford KA, Reid RC, Clark CI, Tyndall JDA, Whitehouse MW, Guthrie T, McGeary RP, Schafer K, Martin JL, Fairlie DP (2003) D-tyrosine as a chiral precursor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (Imia) with antiinflammatory activity. Chembiochem 4:181–185. doi:10.1002/cbic.200390029

    Article  CAS  PubMed  Google Scholar 

  • Hofmann B, Steinhilber D (2013) 5-lipoxygenase inhibitors: a review of recent patents (2010–2012). Expert Opin Ther Pat B:895–909. doi:10.1517/13543776.2013.791678

  • Kang JH, Zheng T, Mr M, Js S, Lee J, Ke D, Hong S, Cui M, Choi S, Hw C, Hy PC, Yim M (2015) 5-lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression. Bioorg Med Chem 23:7069–7078. doi:10.1016/j.bmc. 2015.09.025

    Article  CAS  PubMed  Google Scholar 

  • Kim HH, Kim DH, Kim MH, Oh MH, Kim SR, Park KJ, Lee MW (2013) Flavonoid constituents in the leaves of Myrica rubra Sieb. Et Zucc. With anti-inflammatory activity. Arch Pharm Res 36:1533–1540. doi:10.1007/s12272-013-0147-x

    Article  CAS  PubMed  Google Scholar 

  • Leone S, Ottani A, Bertolini A (2007) Dual acting anti-inflammatory drugs. Curr Top Med Chem 7:265–275

    Article  CAS  PubMed  Google Scholar 

  • Li CS, Brideau C, Chan CC, Savoie C, Claveau D, Charleson S, Gordon R, Greig G, Gauthier JY, Lau CK, Riendeau D, Thérien M, Wong E, Prasit P (2003) Pyridazinones as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 13:597–600. doi:10.1016/S0960-894X(02)01045-4

    Article  CAS  PubMed  Google Scholar 

  • Mayer AM (1989) Manoalide: a new phospholipase A2 inhibitor of marine origin with potential immunoregulatory effect. Med (B Aires) 49:175–180

    CAS  Google Scholar 

  • Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435. doi:10.1038/nature07201

    Article  CAS  PubMed  Google Scholar 

  • Meirer K, Steinhilber D, Proschak E (2014) Inhibitors of the arachidonic acid cascade: interfering with multiple pathways. Basic Clin Pharmacol Toxicol 114:83–91. doi:10.1111/bcpt.12134

    Article  CAS  PubMed  Google Scholar 

  • Montuschi P, Sala A, Dahlén SE, Folco G (2007) Pharmacological modulation of the leukotriene pathway in allergic airway disease. Drug Discov Today 12:404–412. doi:10.1016/j.drudis.2007.03.004

    Article  CAS  PubMed  Google Scholar 

  • Naveen CD, Prasanth GK, Sadasivan C, Haridas M (2013) Evaluation of bio-transformed berberine derivatives as anti-inflammatory drugs: an in silico study. Interdiscip Sci: Comput Life Sci 4:268–272. doi:10.1007/s12539-012-0142-9

    Article  Google Scholar 

  • Oinuma H, Takamura T, Hasegawa T, Nomoto K, Naitoh T, Daiku Y, Hamano S, Kakisawa H, Minami N (1991) Synthesis and biological evaluation of substituted benzenesulfonamides as novel potent membrane-bound phospholipase A2 inhibitors. J Med Chem 34:2260–2267

    Article  CAS  PubMed  Google Scholar 

  • Rao P, Knaus EE (2008) Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci 11:81s–110s

    Article  PubMed  Google Scholar 

  • Rao PPN, Amini M, Li H, Habeeb AG, Knaus EE (2003) Design, synthesis, and biological evaluation of 6-substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors. J Med Chem 46:4872–4882. doi:10.1021/jm0302391

    Article  CAS  Google Scholar 

  • Rao PNP, Uddin MJ, Knaus EE (2004) Design, synthesis, and structure-activity relationship studies of 3,4,6-triphenylpyran-2-ones as selective cyclooxygenase-2 inhibitors. J Med Chem 47:3972–3990. doi:10.1021/jm049939b

    Article  CAS  PubMed  Google Scholar 

  • Rimon G, Sidhu RS, Lauver DA, Lee JY, Sharma NP, Yuan C, Frieler RA, Trievel RC, Lucchesi BR, Smith WL (2011) Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc Natl Acad Sci 107:28–33

    Article  Google Scholar 

  • Rossi A, Pergola C, Koeberle A, Hoffmann M, Dehm F, Bramanti P, Cuzzocrea S, Werz O, Sautebin L (2010) The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages. Br J Pharmacol 161:555–570. doi:10.1111/j.1476-5381.2010.00930.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rouzer CA, Marnett LJ (2009) Cyclooxygenases: structural and functional insights. J Lipid Res 50:S29–S34. doi:10.1194/jlr.R800042-JLR200

    Article  PubMed  PubMed Central  Google Scholar 

  • Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437

    Article  CAS  PubMed  Google Scholar 

  • Snyder DW, Bach NJ, Dillard RD, Draheim SE, Carlson DG, Fox N, Roehm NW, Armstrong CT, Chang CH, Hartley LW, Johnson LM, Roman CR, Smith AC, Song M, Fleisch JH (1999) Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: a new class of anti-inflammatory drugs, SPI. J Pharmacol Exp Ther 288:1117–1124

    CAS  PubMed  Google Scholar 

  • Springer DM, Luh BY, Bronson JJ, McElhone KE, Mansuri MM, Gregor KR, Nettleton DO, Stanley PL, Tramposch KM (2000) Biaryldiacid inhibitors of human s-PLA2 with anti-inflammatory activity. Bioorg Med Chem 8:1087–1109

    Article  CAS  PubMed  Google Scholar 

  • Steinhilber D, Hofmann B (2014) Recent advances in the search for novel 5-lipoxygenase inhibitors. Basic Clin Pharmacol Toxicol 114:70–77

    Article  CAS  PubMed  Google Scholar 

  • Talley JJ (1999) Selective inhibitors of cyclooxygenase-2 (COX-2). Prog Med Chem Res 36:201–234

    Article  CAS  Google Scholar 

  • Tomy MJ, Dileep KV, Prasanth S, Preethidan DS, Sabu A, Sadasivan C, Haridas M (2014a) Cuminaldehyde as a lipoxygenase inhibitor: in vitro and in silico validation. Appl Biochem Biotechnol 174:388–397

    Article  CAS  PubMed  Google Scholar 

  • Tomy MJ, Sharanya CS, Dileep KV, Prasanth S, Sabu A, Sadasivan C, Haridas M (2014b) Derivatives form better lipoxygenase inhibitors than piperine: In vitro and in silico study. Chem Biol Drug Des 85:715–721

    Article  PubMed  Google Scholar 

  • Tramposch KM, Steiner SA, Stanley PL, Nettleton DO, Franson RC, Lewin AH, Carroll FI (1992) Novel inhibitor of phospholipase A2 with topical anti-inflammatory activity. Biochem Biophys Res Commun 189:272–279

    Article  CAS  PubMed  Google Scholar 

  • Tramposch KM, Chilton FH, Stanley PL, Franson RC, Havens MB, Nettleton DO, Davern LB, Darling IM, Bonney RJ (1994) Inhibitor of phospholipase A2 blocks eicosanoid and platelet activating factor biosynthesis and has topical anti-inflammatory activity. J Pharmacol Exp Ther 271:852–859

    CAS  PubMed  Google Scholar 

  • Van Breemen RB, Tao Y, Li W (2011) Cyclooxygenase-2 inhibitors in ginger (Zingiber officinale). Fitoterapia 82:38–43. doi:10.1016/j.fitote.2010.09.004

    Article  PubMed  Google Scholar 

  • Werz O (2004) 5-lipoxygenase: regulation and pharmacology. Med Chem Rev 1(2):201–223. doi:10.2174/1567203043480331

    CAS  Google Scholar 

  • Werz O, Steinhilber D (2005) Development of 5-lipoxygenase inhibitors--lessons from cellular enzyme regulation. Biochem Pharmacol 70:327–333. doi:10.1016/j.bcp.2005.04.018

    Article  CAS  PubMed  Google Scholar 

  • Werz O, Steinhilber D (2006) Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther 112:701–718. doi:10.1016/j.pharmthera.2006.05.009

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Hung TM, Phuong PT, Ngoc TM, Min BS, Song KS, Seong YH, Bae K (2006) Anti-inflammatory activity of flavonoids from Populus davidiana. Arch Pharm Res 29:1102–1108

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann KC, Sarbia M, Schrör K, Weber AA, (1998) Constitutive cyclooxygenase-2 expression in healthy human and rabbit gastric mucosa. Mol Pharmacol 54: 536–540. doi: https://doi.org/10.1124/mol.54.3.536

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Authors and Affiliations

  1. Inter University Centre for Bioscience, Department of Biotechnology and Microbiology, Kannur University, Thalassery Campus, Kannur, Kerala, 670661, India

    C. S. Sharanya & Madathilkovilakath Haridas

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  1. C. S. Sharanya
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  2. Madathilkovilakath Haridas
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Correspondence to Madathilkovilakath Haridas .

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Editors and Affiliations

  1. Microbiology Division, Jawaharlal Nehru Tropical Botanic Garden, Thiruvananthapuram, Kerala, India

    Shiburaj Sugathan

  2. Microbiology Division, Jawaharlal Nehru Tropical Botanic Garden, Thiruvananthapuram, Kerala, India

    N. S. Pradeep

  3. Inter University Centre for Bioscience, Department of Biotechnology and Microbiology, School of Life Sciences, Kannur University, Kannur, Kerala, India

    Sabu Abdulhameed

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Sharanya, C.S., Haridas, M. (2017). Anti-inflammatory Molecules: Enzyme Inhibitors. In: Sugathan, S., Pradeep, N., Abdulhameed, S. (eds) Bioresources and Bioprocess in Biotechnology. Springer, Singapore. https://doi.org/10.1007/978-981-10-4284-3_9

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