Rapid development of two factor IXa inhibitors from hit to lead

Parker, Dann L.; Walsh, Shawn P.; Li, Bing; Kim, Esther; Sharipour, Aurash; Smith, Cameron J.; Chen, Yiheng; Berger, Richard S.; Harper, Bart; Zhang, Ting; Park, Min; Shi, Min; Wu, Jane Y.; Xu, Jiayi; Dewnani, Sunita; Sherer, Edward C.; Hruza, Alan; Reichert, Paul; Geissler, Wayne M.; Sonatore, Lisa M.; Ellsworth, Kenneth; Balkovec, James M.; Greenlee, William J.; Wood, Harold B.

doi:10.1016/j.bmcl.2015.04.025

Cited by 15 publications

(13 citation statements)

References 8 publications

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“…5. From the generated pharmacophore model indicated importance of amino bridge for H-bond interaction with amino acids like GLY216 [10] while aromatic features were found to be responsible for pi-stacking interactions with aromatic amino acids like PHE174 and TYR215.…”

Section: Resultsmentioning

confidence: 99%

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3D QSAR and Pharmacophore Modelling of Selected Benzimidazole Derivatives as Factor IXa Inhibitors

Kumbhar¹,

Choudhari²,

Bhatia³

2017

pharmaceutical-sciences

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Section: Resultsmentioning

confidence: 99%

“…Dataset for the present study was taken from the literature reported by Parker et al [10] . The data set was assorted into a training set (16 molecules) and a test set (7 molecules) using random selection.…”

Section: Methodsmentioning

confidence: 99%

3D QSAR and Pharmacophore Modelling of Selected Benzimidazole Derivatives as Factor IXa Inhibitors

Kumbhar¹,

Choudhari²,

Bhatia³

2017

pharmaceutical-sciences

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“…This suggests that the occupation of the S1 pocket drives the substantial interactions that stabilize the active configuration of FIXa. (B) These interactions, however, seem to be missing in absence of a substrate in the S1 pocket and E219 CT appears to take a closer contact (distance ≈ 4.3 Å; PDB code 4yzu 51 ) with K224 CT…”

Section: Discussionmentioning

confidence: 99%

Probing activation‐driven changes in coagulation factor IX by mass spectrometry

Freato

Alphen

Boon-Spijker

et al. 2021

Journal of Thrombosis and Haemostasis

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“…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%

“…Hence, the selective inhibitor design for FIXa is very critical toward the management of the clinical condition. Many lead optimization programs and a number of experimental data also support the necessity of selective design FIXa inhibitors [ 10 , 11 , 12 , 13 , 14 , 21 , 22 ].…”

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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Rapid development of two factor IXa inhibitors from hit to lead

Cited by 15 publications

References 8 publications

3D QSAR and Pharmacophore Modelling of Selected Benzimidazole Derivatives as Factor IXa Inhibitors

3D QSAR and Pharmacophore Modelling of Selected Benzimidazole Derivatives as Factor IXa Inhibitors

Probing activation‐driven changes in coagulation factor IX by mass spectrometry

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

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