New antithrombin‐based anticoagulants

Desai, Umesh R.

doi:10.1002/med.10058

Cited by 131 publications

(118 citation statements)

References 198 publications

(188 reference statements)

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“…The starting conformation of the L-iduronic acid building unit G in dimers F-G and G-H was set to the more stable skew-boat 2 S o form [4]. This conformation was taken, as it is the prevalent form of this residue in heparin and its model compounds [1,9,16,18]. Initial conformations used in the DFT calculations of the dimers studied were based on the previous calculations of corresponding sodium salts [17].…”

Section: Computational Detailsmentioning

confidence: 99%

“…Heparan sulfates are complex saccharides found on all cell surfaces, which bind selectively to a variety of proteins and pathogens and play important roles in numerous physiological and pathological processes, such as angiogenesis, cancer, hemostasis, growth factor control, anticoagulation, and cell adhesion [1][2][3][4][5]. Many of these activities have been discovered using heparin.…”

Section: Introductionmentioning

confidence: 99%

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Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

2010

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This study reports in detail the results of systematic large-scale theoretical investigations of the acidic dimeric structural units (D-E, E-F, F-G, and G-H) and pentamer D-E-F-G-H (fondaparinux) of the glycosaminoglycan heparin, and their anionic forms. The geometries and energies of these oligomers have been computed using HF/6-31G(d), Becke3LYP/6-31G(d), and Becke3LYP/ 6-311?G(d,p) methods. The optimized geometries indicate that the most stable structure of these units in the neutral state is stabilized via a system of intramolecular hydrogen bonds. The equilibrium structure of these species changed appreciably upon dissociation. Water has a remarkable effect on the geometry of the anions studied. Because of high negative charge, the solvent effect also resulted in an appreciable energetic stabilization of biologically active anionic forms of these glycosaminoglycans. The stable energy conformations around glycosidic bonds found for dimers and pentamer investigated are compared and discussed with the available experimental X-ray structural data for the structurally related heparinderived pentasaccharides in cocrystals with proteins.

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Section: Computational Detailsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

2010

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“…HX3 induces HCII activation nearly 250‐fold, which is almost equal to that AT activation induced by fondaparinux, a clinically used anticoagulant 5, 8. However, HX3 is extremely poor in activating AT (only 5‐fold).…”

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confidence: 94%

“…Likewise, none of these sequences are heparin‐like because their IdoA composition (≈10 %) is much lower than that present in heparin (>80 %). Most interestingly, all three sequences contain one or more GlcA2S and GlcNS3S residues, which are rare in natural HS, but known to target AT in a selective manner 5, 6, 18. Our CVLS algorithm predicted HX1, HX2 and HX3 to bind to activated HCII in an essentially identical orientation with an RMSD of only 1.6 Å (Figures 2 a and S3).…”

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confidence: 95%

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A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II

et al. 2017

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Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2‐O‐sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250‐fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG‐binding protein(s), which may lead to chemical biology or drug discovery tools.

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Anticoagulants

Henry

Desai

2010

Burger's Medicinal Chemistry and Drug Discovery

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Thrombotic disorders are a major cause of morbidity and mortality in humans. Examples of thrombotic disorders include pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, acute myocardial infarction, unstable angina, and cerebrovascular thrombosis. Anticoagulants are the mainstay of treatment and prevention of these disorders. The most widely used anticoagulants include unfractionated heparin, low molecular weight heparins and warfarin. Newer agents introduced in the past decade include bivalirudin, fondaparinux, and argatroban. Mechanistically, these anticoagulants either directly inhibit thrombin or indirectly reduce the activity of thrombin and factor Xa. Several new molecules have been recently designed to directly inhibit thrombin and factor Xa with high potency and considerable selectivity, of which dabigatran and rivaroxaban were approved for clinical use in few countries in 2008. Molecules being pursued in clinical trials include AZD0837, LB‐30870, otamixaban, apixaban, YM‐150, and others. Ximelagatran, which was introduced in 2004 as a direct thrombin inhibitor, was taken off the market within 20 months due to significant hepatotoxicity. Indirect anticoagulants utilize the antithrombin‐mediated conformational activation and bridging mechanisms for inhibiting coagulation enzymes. Among the indirect anticoagulants that are currently being investigated in clinical trials are a biotinylated idraparinux and SR123781. Over the last two decades, major conceptual strides have been made including the design of the first anticoagulant based solely on factor Xa inhibition (fondaparinux) and the establishment of the paradigm that anticoagulation is possible without frequent laboratory monitoring (ximelagatran). Current work attempts to establish other concepts such as the dual inhibition of free and clot‐bound thrombin by a heparin‐based molecule (ORG42675) and the applicability of neutral P1‐group containing active site‐directed molecules as effective inhibitors of coagulation enzymes (rivaroxaban). To date, no molecule has been designed that satisfies all the properties of an ideal anticoagulant including a broad therapeutic window, absence of bleeding risk, no requirement for frequent coagulation monitoring, oral bioavailability, availability of an effective antidote, lack of hepatoxicity and absence other adverse effects. Yet, the newer agents are likely to be more attractive than the heparin‐ and coumarin‐based therapy. In this chapter, we review the structure, design, and mechanism of action of clinically used and new potential anticoagulants. Special emphasis is placed on the molecular interaction of anticoagulants with their targets.

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New antithrombin‐based anticoagulants

Cited by 131 publications

References 198 publications

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II

Anticoagulants

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