Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa:  Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity

Wiley, Michael R.; Weir, Leonard C.; Briggs, Stephen L.; Bryan, Nancy; Buben, John A.; Campbell, Charles S.; Chirgadze, Nickolay Y.; Conrad, Richard C.; Craft, Trelia J.; Ficorilli, James; Franciskovich, Jeffry B.; Froelich, Larry L.; Gifford‐Moore, Donetta S.; Goodson, Theodore; Herron, David K.; Klimkowski, V. J.; Kurz, K D; Kyle, Jeffery A.; Masters, John J.; Ratz, Andrew M.; Milot, Guy; Shuman, Robert T.; Smith, Tommy; Smith, Gary; Tebbe, Ann Louise; Tinsley, Jennifer M.; Towner, Richard D.; Wilson, Andy; Yee, Ying K.

doi:10.1021/jm9903287

Cited by 46 publications

(25 citation statements)

References 42 publications

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“…But if we consider again the factor Xa thrombin pairing, we can find an explanation for this result. Formerly, when the crystallization of factor Xa was not possible, medicinal chemists often used thrombin as a surrogate protein for the design of new factor Xa inhibitors [48]. Consequently, it is not so surprising that the virtual screening performance of our method is independent of whether factor Xa or thrombin is used as the target structure.…”

Section: Null Hypothesis Performancementioning

confidence: 99%

Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

Schneider

Hindle²,

Lange

et al. 2011

J Comput Aided Mol Des

131

100

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The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein-ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom-based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein-ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets.

show abstract

Section: Null Hypothesis Performancementioning

confidence: 99%

Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

Schneider

Hindle²,

Lange

et al. 2011

J Comput Aided Mol Des

131

100

View full text Add to dashboard Cite

show abstract

“…200 The amidine in 184 (fXa K ass 5 250 Â 10 6 L/mol, fXa K i $4 nM) improved the potency by about 250-fold, and installation of a carboxylic acid in 185 (fXa K ass 5 470 Â 10 6 L/mol, fXa K i $2.2 nM) further doubled the potency of 184. Both compounds showed in vitro anticoagulant activities with EC 2 Â PT values of 0.96 and 0.83 mM, respectively.…”

Section: Group 5 Anthranilamides Disubstituted Benzenes and Diaminmentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.

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“…Methyl-3-aminothiophene-2-carboxylate (matc) is a significantly important intermediate in pharmaceutical products such as anti-hypertensives [1,2], antitumors [3], anti-HIV-1 integrase [4], human cytomegalovirus inhibitors [5], hepatitis C virus inhibitors [6], Xa factor inhibitors [7], antineoplastic PAK4 activase inhibitors [8], phosphatidylinositol 3-kinase PI3K inhibitors [9], and antithrombotic activity drugs [10]. It is also a key starting material in agrochemical products, providing herbicidal protection through thiafulone or the sulfonylurea herbicide [11].…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure and Computational Study on Methyl-3-Aminothiophene-2-Carboxylate

et al. 2020

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Methyl-3-aminothiophene-2-carboxylate (matc) is a key intermediate in organic synthesis, medicine, dyes, and pesticides. Single crystal X-ray diffraction analysis reveals that matc crystallizes in the monoclinic crystal system P21/c space group. Three matc molecules in the symmetric unit are crystallographically different and further linked through the N–H⋯O and N–H⋯N hydrogen bond interactions along with weak C–H⋯S and C–H⋯Cg interactions, which is verified by the three-dimensional Hirshfeld surface, two-dimensional fingerprint plot, and reduced density gradient (RDG) analysis. The interaction energies within crystal packing are visualized through dispersion, electrostatic, and total energies using three-dimensional energy-framework analyses. The dispersion energy dominates in crystal packing. To better understand the properties of matc, electrostatic potential (ESP) and frontier molecular orbitals (FMO) were also calculated and discussed. Experimental and calculation results suggested that amino and carboxyl groups can participate in various inter- and intra-interactions.

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Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa: Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity

Cited by 46 publications

References 42 publications

Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Crystal Structure and Computational Study on Methyl-3-Aminothiophene-2-Carboxylate

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