Design of selective phenylglycine amide tissue factor/factor VIIa inhibitors

Zbinden, Katrin Groebke; Banner, David W.; Ackermann, Jean; D’Arcy, Allan; Kirchhofer, Daniel; Ji, Yuhua; Tschopp, Thomas B.; Wallbaum, Sabine; Weber, Lutz

doi:10.1016/j.bmcl.2004.10.092

Cited by 32 publications

(15 citation statements)

References 40 publications

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“…The crystal structures of fourteen targets were retrieved from the Protein Data Bank (PDB entries: 1FJS[37], 1TA2[38], 1RFN[39], 1W0Y[40], 1YGC[41], 2HLO, 2ANW[42], 1TFH[43], 1K22[44], 1AUQ[45], 3CDZ[46], 2F83[47], 1FZG[48] and 1GGT[49]). Hetero atoms were removed from the receptors, and then hydrogen atoms were added and wrong valence shells were corrected using Discovery Studio.…”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

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

et al. 2011

PLoS ONE

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“…The intermediate ethyloxyimidine 77 has to be extensively hydrolyzed and the isocyanide only contributes the carbon resulting in the carboxylic carbonyl. 66 …”

Section: Mcrs By Target Classmentioning

confidence: 99%

Chemistry and Biology Of Multicomponent Reactions

2012

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“…In addition to their good inhibitory activity, Bioorganic & Medicinal Chemistry Letters 15 (2005) Crystals of compound 1 complexed with TF/F.VIIa were originally produced as described. 10 Crystals of the complex of 1 with short form recombinant F.VIIa were produced as described 12 , except that the enzyme was activated before complex formation. Crystals were measured on the Swiss Norwegian Beam Lines (SNBL) at the ESRF, Grenoble, to resolutions of 2.5 Å and 2.85 Å , respectively.…”

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confidence: 99%