Exploration of binding site pattern in arachidonic acid metabolizing enzymes, Cyclooxygenases and Lipoxygenases
TL;DR: It has been identified that aliphatic and aromatic interactions are the most common in all the enzymes and in addition interactions unique to each one of these enzymes were identified.
Abstract: Cyclooxygenase (COXs) and Lipoxygenase (LOXs) pathways are the two major enzymatic pathways in arachidonic acid (AA) metabolism. The term eicosanoid is used to describe biologically active lipid mediators including prostaglandins, thromboxanes, leukotrienes and other oxygenated derivatives, which are produced primarily from AA. Eicosanoids generated in a tissue specific manner play a key role in inflammation and cancer. As AA is the substrate common to variety of COXs and LOXs, inhibition of one pathway results in diversion of the substrate to other pathways, which often is responsible for undesirable side effects. Hence there is need for development of not only isozyme specific inhibitors but also dual/multi enzyme inhibitors. Understanding the interactions of AA and characterizing its binding sites in these enzymes therefore is crucial for developing enzyme specific and multi enzyme inhibitors for enhancing therapeutic efficacy and/or overcoming side effects. AA binding sites in COXs and LOXs are identified and compared by the development of receptor based pharmacophore using MultiBind. Physico chemical properties were compared to understand the details of the binding sites in all the enzymes and to elucidate important amino acids that can be targeted for drug design. The alignment of AA binding sites in the seven enzymes COX-1, COX-2, 5-LOX, 12-LOX, 15-LOX and plant soybean LOX-1 and LOX-3 indicated a common pattern of five common interacting groups. In the same way, comparison of AA binding sites was done pair wise and by multiple alignment in various combinations. It has been identified that aliphatic and aromatic interactions are the most common in all the enzymes. In addition interactions unique to each one of these enzymes were identified. The complete analysis of AA binding sites in the seven enzymes was performed; 120 combinations for the seven enzymes were studied in detail. All the seven enzymes are structurally quite different, yet they share AA as the common binding partner. Comparisons in various combinations showed how they are similar and dissimilar with each other. This information will be helpful in designing specific as well as common inhibitors.
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TL;DR: Seven coumarin derivatives synthesized using various aromatic and heterocyclic amines were evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk, and revealed that compound 33 and 35 are the most potent compounds in all the screening methods.
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TL;DR: In silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs.
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TL;DR: In this article, the role of arachidonic acid (AA) metabolism in cardiovascular health and disease as well as their potential therapeutic implication is reviewed, including the role played by different AA metabolites in the modulation of vascular tone and cardiovascular complications.
Abstract: Arachidonic acid (AA) is an essential fatty acid that is released by phospholipids in cell membranes and metabolized by cyclooxygenase (COX), cytochrome P450 (CYP) enzymes, and lipid oxygenase (LOX) pathways to regulate complex cardiovascular function under physiological and pathological conditions. Various AA metabolites include prostaglandins, prostacyclin, thromboxanes, hydroxyeicosatetraenoic acids, leukotrienes, lipoxins, and epoxyeicosatrienoic acids. The AA metabolites play important and differential roles in the modulation of vascular tone, and cardiovascular complications including atherosclerosis, hypertension, and myocardial infarction upon actions to different receptors and vascular beds. This article reviews the roles of AA metabolism in cardiovascular health and disease as well as their potential therapeutic implication.
33 citations
TL;DR: In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated.
26 citations
References
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TL;DR: Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
Abstract: Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
8,204 citations
"Exploration of binding site pattern..." refers background in this paper
...There are three COX isoforms, COX-1, COX-2, and COX-3 [1-3]....
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...COX-3, a product of COX-1 gene has been identified as the alternatively spliced form found mostly in the brain....
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...In a recent study, Doble et al. have done a comparative study of PGH2 binding site in prostaglandin synthases [23]....
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...It introduces two molecules of oxygen into AA to form PGG2, a cyclic hydroperoxy endoperoxide, which is subsequently reduced by peroxidase to give hydroxy endoperoxide, PGH2 [2]....
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TL;DR: GOLD (Genetic Optimisation for Ligand Docking) is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding.
5,882 citations
"Exploration of binding site pattern..." refers methods in this paper
...GOLD (Genetic Optimization of Ligand Docking), a docking program based on genetic algorithm [31] was used to dock the substrate i....
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TL;DR: Important insights into the mechanisms of inflammatory responses, pain, and fever have been gleaned from the current understanding of eicosanoid biology.
Abstract: Prostaglandins and leukotrienes are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and actions are blocked by clinically relevant nonsteroidal anti-inflammatory drugs, the newer generation coxibs (selective inhibitors of cyclooxygenase-2), and leukotriene modifiers. The prime mode of prostaglandin and leukotriene action is through specific G protein-coupled receptors, many of which have been cloned recently, thus enabling specific receptor agonist and antagonist development. Important insights into the mechanisms of inflammatory responses, pain, and fever have been gleaned from our current understanding of eicosanoid biology.
3,505 citations
"Exploration of binding site pattern..." refers background in this paper
...LOXs are broadly classified as 5-, 12, and 15-LOXs in animals [10,11] based on regio and stereo specific incorporation of molecular oxygen on AA....
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TL;DR: A new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity.
Abstract: The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.
2,915 citations
"Exploration of binding site pattern..." refers background in this paper
...and potential side effects have been removed [19]....
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...Multitarget drug design is gaining prominence in modern drug discovery and in silico approaches may play a very crucial role in such approaches [19]....
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TL;DR: 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis, is identified.
Abstract: A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
1,895 citations
"Exploration of binding site pattern..." refers background in this paper
...Celecoxib shows 375-fold selectivity towards COX-2 over COX-1 [20]....
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