Direct thrombin inhibitors: Patents 2002–2012 (Review)

Kong, Yi; Chen, Hao; Wang, Yongqing; Meng, Ling; Wei, Ji‐Fu

doi:10.3892/mmr.2014.2025

Cited by 21 publications

(8 citation statements)

References 73 publications

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“…Thrombin (T23) is predicted to be druggable both by Cheng et al 8 and by FTMap, and now has direct (i.e., not prodrug) oral inhibitors. 103,104 With 15 probe clusters, the penicillin binding protein (T22) is borderline druggable by FTMap, and ligand binding substantially strengthens the hot spot. This protein binds piperacillin, 105 an approved but not orally bioavailable drug (MW= 517.5 g/mol), with an IC 50 of 166 nM.…”

Section: Introductionmentioning

confidence: 99%

New Frontiers in Druggability

Kozakov

Hall

Napoleon³

et al. 2015

J. Med. Chem.

162

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A powerful early approach to evaluating the druggability of proteins involved determining the hit rate in NMR-based screening of a library of small compounds. Here we show that a computational analog of this method, based on mapping proteins using small molecules as probes, can reliably reproduce druggability results from NMR-based screening, and can provide a more meaningful assessment in cases where the two approaches disagree. We apply the method to a large set of proteins. The results show that, because the method is based on the biophysics of binding rather than on empirical parameterization, meaningful information can be gained about classes of proteins and classes of compounds beyond those resembling validated targets and conventionally druglike ligands. In particular, the method identifies targets that, while not druggable by druglike compounds, may become druggable using compound classes such as macrocycles or other large molecules beyond the rule-of-five limit.

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Section: Introductionmentioning

confidence: 99%

New Frontiers in Druggability

Kozakov

Hall

Napoleon³

et al. 2015

J. Med. Chem.

162

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“…Compared with heparins, DTIs do not require antithrombin as a cofactor and do not bind to plasma proteins; therefore, they produce a more predictable anticoagulant effect, and variability of patient response is low relative to other drug classes [ 9 ]. In reality, they still present limitations such as a narrow therapeutic window, and bleeding and anaphylaxis as side effects [ 10 ]. Therefore, alternative antithrombotic therapies are under extensive investigation, and many entities from natural products are being isolated and studied to counteract these side effects [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Investigation of Interactions between Thrombin and Ten Phenolic Compounds by Affinity Capillary Electrophoresis and Molecular Docking

Yang

et al. 2018

Journal of Analytical Methods in Chemistry

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Thrombin plays a vital role in blood coagulation, which is a key process involved in thrombosis by promoting platelet aggregation and converting fibrinogen to form the fibrin clot. In the receptor concept, drugs produce their therapeutic effects via interactions with the targets. Therefore, investigation of interaction between thrombin and small molecules is important to find out the potential thrombin inhibitor. In this study, affinity capillary electrophoresis (ACE) and in silico molecular docking methods were developed to study the interaction between thrombin and ten phenolic compounds (p-hydroxybenzoic acid, protocatechuic acid, vanillic acid, gallic acid, catechin, epicatechin, dihydroquercetin, naringenin, apigenin, and baicalein). The ACE results showed that gallic acids and six flavonoid compounds had relative strong interactions with thrombin. In addition, the docking results indicated that all of optimal conformations of the six flavonoid compounds were positioned into the thrombin activity centre and had interaction with the HIS57 or SER195 which was the key residue to bind thrombin inhibitors such as argatroban. Herein, these six flavonoid compounds might have the potential of thrombin inhibition activity. In addition, the developed method in this study can be further applied to study the interactions of other molecules with thrombin.

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“…In 2002, Mollnes et al described an in vitro human whole blood model to study the role of the complement system in sepsis (14). The anticoagulant used in this model is lepirudin, a recombinant form of hirudin derived from leeches that acts on thrombin and does not affect complement system activity (15). This model allows for the analysis of the role of complement activation in the production of inflammatory cytokines and chemokines and in the expression of activation molecules by leukocytes (14, 16).…”

Section: Introductionmentioning

confidence: 99%

Complement System Inhibition Modulates the Pro-Inflammatory Effects of a Snake Venom Metalloproteinase

et al. 2019

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Envenomation by Bothrops snakes causes prominent local effects, including pain, oedema, local bleeding, blistering and necrosis, and systemic manifestations, such as hemorrhage, hypotension, shock and acute renal failure. These snake venoms are able to activate the complement system and induce the generation of anaphylatoxins, whose mechanisms include the direct cleavage of complement components by snake venom metalloproteinases and serine proteinases present in the venoms. A metalloproteinase able to activate the three complement pathways and generate active anaphylatoxins, named C-SVMP, was purified from the venom of Bothrops pirajai . Considering the inflammatory nature of Bothrops venoms and the complement-activation property of C-SVMP, in the present work, we investigated the inflammatory effects of C-SVMP in a human whole blood model. The role of the complement system in the inflammatory process and its modulation by the use of compstatin were also investigated. C-SVMP was able to activate the complement system in the whole blood model, generating C3a/C3a desArg, C5a/C5a desArg and SC5b-9. This protein was able to promote an increase in the expression of CD11b, CD14, C3aR, C5aR1, TLR2, and TLR4 markers in leukocytes. Inhibition of component C3 by compstatin significantly reduced the production of anaphylatoxins and the Terminal Complement Complex (TCC) in blood plasma treated with the toxin, as well as the expression of CD11b, C3aR, and C5aR on leukocytes. C-SVMP was able to induce increased production of the cytokines IL-1β and IL-6 and the chemokines CXCL8/IL-8, CCL2/MCP-1, and CXCL9/MIG in the human whole blood model. The addition of compstatin to the reactions caused a significant reduction in the production of IL-1β, CXCL8/IL-8, and CCL2/MCP-1 in cells treated with C-SVMP. We therefore conclude that C-SVMP is able to activate the complement system, which leads to an increase in the inflammatory process. The data obtained with the use of compstatin indicate that complement inhibition may significantly control the inflammatory process initiated by Bothrops snake venom toxins.

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Direct thrombin inhibitors: Patents 2002–2012 (Review)

Cited by 21 publications

References 73 publications

New Frontiers in Druggability

New Frontiers in Druggability

Investigation of Interactions between Thrombin and Ten Phenolic Compounds by Affinity Capillary Electrophoresis and Molecular Docking

Complement System Inhibition Modulates the Pro-Inflammatory Effects of a Snake Venom Metalloproteinase

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