Computer Design of Low-Molecular-Weight Inhibitors of Coagulation Factors

Kabankin, A. S.; Sinauridze, Elena I.; Lipets, Elena N.; Ataullakhanov, F. I.

doi:10.1134/s0006297919020032

Cited by 4 publications

(5 citation statements)

References 59 publications

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“…Blood coagulation plays a crucial role in maintaining hemostasis. However, deviations from normal coagulation can have severe consequences, leading to a range of coagulationassociated disorders [1][2][3]. Among these disorders, atrial fibrillation stands out as a significant contributor, as it promotes the formation of blood clots, thereby precipitating various clinical pathological conditions, including arterial [4] and venous thrombosis [5], heart attacks, ischemic strokes [6], pulmonary embolisms [7], and cardiac strokes [8].…”

Section: Introductionmentioning

confidence: 99%

“…Among these disorders, atrial fibrillation stands out as a significant contributor, as it promotes the formation of blood clots, thereby precipitating various clinical pathological conditions, including arterial [4] and venous thrombosis [5], heart attacks, ischemic strokes [6], pulmonary embolisms [7], and cardiac strokes [8]. Collectively, these conditions fall under the category of thromboembolic disorders, which continue to pose substantial threats to both mortality and disability rates in the modern era [1][2][3]. In addressing these disorders, anticoagulants have emerged as the established treatment and can effectively manage thromboembolic disorders and improve patient condition.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics Simulation Study of the Selective Inhibition of Coagulation Factor IXa over Factor Xa

Yoon,

Kundu,

2023

Molecules

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Thromboembolic disorders, arising from abnormal coagulation, pose a significant risk to human life in the modern world. The FDA has recently approved several anticoagulant drugs targeting factor Xa (FXa) to manage these disorders. However, these drugs have potential side effects, leading to bleeding complications in patients. To mitigate these risks, coagulation factor IXa (FIXa) has emerged as a promising target due to its selective regulation of the intrinsic pathway. Due to the high structural and functional similarities of these coagulation factors and their inhibitor binding modes, designing a selective inhibitor specifically targeting FIXa remains a challenging task. The dynamic behavior of protein–ligand interactions and their impact on selectivity were analyzed using molecular dynamics simulation, considering the availability of potent and selective compounds for both coagulation factors and the co-crystal structures of protein–ligand complexes. Throughout the simulations, we examined ligand movements in the binding site, as well as the contact frequencies and interaction fingerprints, to gain insights into selectivity. Interaction fingerprint (IFP) analysis clearly highlights the crucial role of strong H-bond formation between the ligand and D189 and A190 in the S1 subsite for FIXa selectivity, consistent with our previous study. This dynamic analysis also reveals additional FIXa-specific interactions. Additionally, the absence of polar interactions contributes to the selectivity for FXa, as observed from the dynamic profile of interactions. A contact frequency analysis of the protein–ligand complexes provides further confirmation of the selectivity criteria for FIXa and FXa, as well as criteria for binding and activity. Moreover, a ligand movement analysis reveals key interaction dynamics that highlight the tighter binding of selective ligands to the proteins compared to non-selective and inactive ligands.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation Study of the Selective Inhibition of Coagulation Factor IXa over Factor Xa

Yoon,

Kundu,

2023

Molecules

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“…Generally, they are present in the plasma in an inactive state but can be activated. Therefore, the coagulation process is a complex cascade of enzymatic reactions that can be activated via both intrinsic and extrinsic pathways 7 . The final step in coagulation is the formation of the fibrin clot from fibrinogen, by the action of thrombin, which acts as a serine protease, which is generated by prothrombin through factor Xa 8 .…”

Section: Introductionmentioning

confidence: 99%

An in-Silico Study of Some Natural and Synthetic Compounds as Potential Inhibitors for Factor Xa

صباغ

AlBeik²,

Hadid³

2022

Bulletin of Pharmaceutical Sciences. Assiut

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Recent research has demonstrated the significance of factor Xa and its inhibitors as a possible treatment approach. Since currently approved drugs have a wide variety of side effects, new anticoagulants must be developed. So, the goal of this in silico research is to find molecules that may act as factor Xa inhibitors. The structure of factor Xa (2w26) was obtained from the Protein Data Bank database, while the structures of the organic compounds were obtained from the ZINC database or via other means. In order to verify the anti-factor Xa action of these chemical compounds, iGemDock program was used to perform molecular docking. The compound ( 1) [5-hydroxy-2-(3-hydroxy-4-phenylmethoxyphenyl)-3,7bis(phenylmethoxy)chromen-4-one] showed the best interaction value against the 2w26 enzyme, and the binding energy was (-167.702 kcal/ mol); whereas the reference rivaroxaban was (-149.661 kcal/mol). These results lead to suggest new organic compounds as factor Xa inhibitors and further in vitro studies are required to confirm.

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“…All these conditions are, in general, categorized as thromboembolic disorders which continues to be one of the major causes of mortality and disability in the modern world. Anticoagulants are the established treatments to manage thromboembolic disorders [ 1 , 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Selective inhibition of FIXa that falls under the intrinsic pathway, which is right above FXa in the downstream coagulation propagation ( Figure S1 , shown in the Supplementary Materials ), is hypothesized and validated for improved bleeding related risk with similar efficacy compared to the FXa inhibitors. The basic tenet of this strategy is the selective regulation of the intrinsic pathway through selective therapeutic agents that would not be affecting the targets in the extrinsic pathway and the common pathway [ 1 , 2 , 3 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

Kundu

2021

Molecules

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Blood coagulation is an essential physiological process for hemostasis; however, abnormal coagulation can lead to various potentially fatal disorders, generally known as thromboembolic disorders, which are a major cause of mortality in the modern world. Recently, the FDA has approved several anticoagulant drugs for Factor Xa (FXa) which work via the common pathway of the coagulation cascade. A main side effect of these drugs is the potential risk for bleeding in patients. Coagulation Factor IXa (FIXa) has recently emerged as the strategic target to ease these risks as it selectively regulates the intrinsic pathway. These aforementioned coagulation factors are highly similar in structure, functional architecture, and inhibitor binding mode. Therefore, it remains a challenge to design a selective inhibitor which may affect only FIXa. With the availability of a number of X-ray co-crystal structures of these two coagulation factors as protein–ligand complexes, structural alignment, molecular docking, and pharmacophore modeling were employed to derive the relevant criteria for selective inhibition of FIXa over FXa. In this study, six ligands (three potent, two selective, and one inactive) were selected for FIXa inhibition and six potent ligands (four FDA approved drugs) were considered for FXa. The pharmacophore hypotheses provide the distribution patterns for the principal interactions that take place in the binding site. None of the pharmacophoric patterns of the FXa inhibitors matched with any of the patterns of FIXa inhibitors. Based on pharmacophore analysis, a selectivity of a ligand for FIXa over FXa may be defined quantitatively as a docking score of lower than −8.0 kcal/mol in the FIXa-grids and higher than −7.5 kcal/mol in the FXa-grids.

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Computer Design of Low-Molecular-Weight Inhibitors of Coagulation Factors

Cited by 4 publications

References 59 publications

Molecular Dynamics Simulation Study of the Selective Inhibition of Coagulation Factor IXa over Factor Xa

Molecular Dynamics Simulation Study of the Selective Inhibition of Coagulation Factor IXa over Factor Xa

An in-Silico Study of Some Natural and Synthetic Compounds as Potential Inhibitors for Factor Xa

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

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