Dual Inhibitors of the Blood Coagulation Enzymes

Kranjc, Andreja; Kikelj, D.

doi:10.2174/0929867043364432

Cited by 24 publications

(12 citation statements)

References 39 publications

(71 reference statements)

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“…When computed by applying the single target docking scores, the correlation coefficients of the estimated potency and the experimental data for factor Xa and thrombin, which are supposed as very important enzymes in clotting cascade[56], [58], [59], [60], were 0.648 and 0.602(Figure 3B and Figure 3C), respectively. However, the correlation between the predicted network efficiencies and the experimental data was improved by applying the multi-target docking scores (r = 0.671) (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

et al. 2011

PLoS ONE

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BackgroundTraditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target.MethodologyWe developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery.ConclusionsThis article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking.

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Section: Resultsmentioning

confidence: 99%

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

et al. 2011

PLoS ONE

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“…2). The size and the shape of the S 1 pocket is quite similar to those in thrombin, factor Xa and trypsin [30]. Factor VIIa differs from thrombin and factor Xa at residue 190, which is Ser in factor VIIa but Ala in thrombin and factor Xa [31].…”

Section: Structure Of Factor Viia and The Role Of Tissue Factor In Rementioning

confidence: 68%

Recent Advances in the Discovery of Tissue Factor/Factor VIIa Inhibitors and Dual Inhibitors of Factor VIIa/Factor Xa

Kranjc¹,

Kikelj²,

Mašič

2005

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The search for an ideal anticoagulant has spanned decades and has taken several approaches to the identification of novel target molecules for preventing and treating thrombosis. In the group of anticoagulants acting through direct inhibition of coagulation factors, most research has focused on thrombin and factor Xa inhibitors. Attention has been drawn most recently to factor VIIa as a promising anticoagulation target, because of its role in complex with tissue factor, in initiating the coagulation cascade following blood vessel damage. Several reports suggest that inhibitors of the tissue factor/factor VIIa complex prevent thrombosis with a lower bleeding risk than other types of inhibitors. Accordingly, there is increasing interest in the generation of potent and selective small-molecule factor VIIa inhibitors that can be safely administered once or twice daily in an oral formulation with no need for routine coagulation monitoring. The emphasis of this review will be placed on recent advances in the development of the small-molecule inhibitors of factor VIIa complexed with tissue factor. The role of factor VIIa and tissue factor as initiators of the coagulation cascade following blood vessel damage is described, along with the structure of the active site of factor VIIa.

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“…Aus diesem Grunde haben mehrere Gruppen begonnen, auch nach dualen Inhibitoren zu suchen. [67] Boehringer Ingelheim berichtete 2001, dass die 1-Methylbenzimidazoleinheit einer Reihe ihrer Inhibitoren in der Lage ist, sowohl die kleine, für Lösungsmittel zugängliche Tasche in Faktor Xa wie auch die größere, hydrophobe S2-Tasche in Thrombin auszufüllen. [68] Einer der potentesten dualen Inhibitoren ist hierbei BIBM1015 (40; Schema 18).…”

Section: Duale Thrombin/faktor-xa-inhibitorenunclassified

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

2011

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Bislang müssen sich Patienten zur Vorbeugung von Thrombosen nach Operationen täglich Heparin spritzen oder müssen zur Schlaganfallprophylaxe bei Vorhofflimmern Vitamin‐K‐Antagonisten vom Cumarintyp einnehmen, die eine geringe therapeutische Breite haben und deren Dosierung regelmäßig überwacht werden muss. Um den Therapiestandard bei thromboembolischen Erkrankungen, wie tiefen Venenthrombosen, Lungenembolien und Hirnschlag bei Vorhofflimmern, zu verbessern, wurde in der letzten Dekade intensiv an neuen, oral wirksamen Thrombin‐ und Faktor‐Xa‐Inhibitoren geforscht. Einige dieser Verbindungen sind bereits auf dem Markt oder befinden sich in fortgeschrittener klinischer Entwicklung; sie könnten den Antikoagulantienmarkt revolutionieren.

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Dual Inhibitors of the Blood Coagulation Enzymes

Cited by 24 publications

References 39 publications

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

Recent Advances in the Discovery of Tissue Factor/Factor VIIa Inhibitors and Dual Inhibitors of Factor VIIa/Factor Xa

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

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