Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors

Bouckaert, Charlotte; Serra, Silvia; Rondelet, G.; Dolušić, Eduard; Dogné, Jean‐Michel; Frédérick, Raphaël; Pochet, Lionel

doi:10.1016/j.ejmech.2016.01.023

Cited by 43 publications

(41 citation statements)

References 49 publications

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“…The docking study was based on the available crystal structures of CTI (Protein Data Bank [PDB]: 1BFA and 1BEA) and on the crystal structure of the FXII protease in a zymogen‐like state that we previously described and termed FXIIac (PDB: 4XE4) and FXIIc (PDB: 4XDE). To generate a structure for the activated conformation of the FXIIa protease, a hybrid model of FXIIa was created with a similar approach to that used by previous authors . Step 1 used the crystal structure of closest homolog HGFA (PDB: 1YC0) as a template in the program swiss‐model to generate coordinates required for the active FXIIa S1 pocket (including residues 16–26, 133–147, 179–189, and 190–224; residue numbers according to the chymotrypsin numbering).…”

Section: Methodsmentioning

confidence: 99%

“…S1). Unlike previous authors , who used the FXIIc coordinates (PDB: 4XDE), we utilized FXIIac (PDB: 4XE4), in which the closed H1 pocket is likely to be the dominant conformation . This model was regularized in coot , and superposed onto typical activated protease crystal structures of thrombin, trypsin, FXa and FXIa to check the positions of key conserved amino acids such as Asp189 in the S1 pocket and Trp215 in the S3 pocket, and to confirm that the N‐terminal Ile16 is correctly described.…”

Section: Methodsmentioning

confidence: 99%

“…The docking study was based on the available crystal structures of CTI [23,24] (Protein Data Bank [PDB]: 1BFA and 1BEA) and on the crystal structure of the FXII protease in a zymogen-like state that we previously described and termed FXIIac (PDB: 4XE4) and FXIIc (PDB: 4XDE). To generate a structure for the activated conformation of the FXIIa protease, a hybrid model of FXIIa was created with a similar approach to that used by previous authors [30].…”

Section: Docking Of Cti and The Fxii Protease Domainmentioning

confidence: 99%

See 2 more Smart Citations

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation

Hamad

Pathak

Manna

et al. 2017

Journal of Thrombosis and Haemostasis

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Essentials Corn Trypsin Inhibitor (CTI) is a selective inhibitor of coagulation Factor XII (FXII).Molecular modelling of the CTI‐FXIIa complex suggested a canonical inhibitor binding mode.Mutagenesis revealed the CTI inhibitory loop and helices α1 and α2 mediate the interaction.This confirms that CTI inhibits FXII in canonical fashion and validates the molecular model. SummaryBackgroundCorn trypsin inhibitor (CTI) has selectivity for the serine proteases coagulation factor XII and trypsin. CTI is in widespread use as a reagent that specifically inhibits the intrinsic pathway of blood coagulation but not the extrinsic pathway.ObjectivesTo investigate the molecular basis of FXII inhibition by CTI.MethodsWe performed molecular docking of CTI, using its known crystal structure, with a model of the activated FXII (FXIIa) protease domain. The interaction model was verified by use of a panel of recombinant CTI variants tested for their ability to inhibit FXIIa enzymatic activity in a substrate cleavage assay.ResultsThe docking predicted that: (i) the CTI central inhibitory loop P1 Arg34 side chain forms a salt bridge with the FXIIa S1 pocket Asp189 side chain; (ii) Trp22 from CTI helix α1 interacts with the FXIIa S3 pocket; and (iii) Arg43 from CTI helix α2 forms a salt bridge with FXIIa H1 pocket Asp60A. CTI amino acid substitution R34A negated all inhibitory activity, whereas the G32W, L35A, W22A and R42A/R43A substitutions reduced activity by large degrees of 108‐fold, 41‐fold, 158‐fold, and 100‐fold, respectively; the R27A, W37A, W39A and R42A substitutions had no effect. Synthetic peptides spanning CTI residues 20–44 had inhibitory activity that was three‐fold to 4000‐fold less than that of full‐length CTI.ConclusionsThe data confirm the validity of a canonical model of the FXIIa–CTI interaction, with helix α1 (Trp22), central inhibitory loop (Arg34) and helix α2 (Arg43) of CTI being required for effective binding by contacting the S1, S3 and H1 pockets of FXIIa, respectively.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Docking Of Cti and The Fxii Protease Domainmentioning

confidence: 99%

See 1 more Smart Citation

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation

Hamad

Pathak

Manna

et al. 2017

Journal of Thrombosis and Haemostasis

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“…Small molecules have a number of strengths that make them attractive for drug development, including a uniform composition, efficient tissue penetration, high stability, low immunoreactivity, and ease of production by chemical synthesis. The best small molecule FXIIa inhibitors reported to date are the coumarin derivative 44 (IC 50 = 4.4 μM) 32 and H-D-Pro-Phe-Arg-chloromethylketone (PCK; IC 50 = 0.18 μM) 10 . While they have proven to be useful as research compounds in FXIIa inhibition studies, their covalent inhibition mechanism and their moderate potency and selectivity limit their drug development potential.…”

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confidence: 99%

Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs

et al. 2020

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Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knockout or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with subnanomolar activity (K i = 370 ± 40 pM) and a high stability (t 1/2 > 5 days in plasma), allowing for the preclinical evaluation of a first synthetic FXIIa inhibitor. This 1899 Da molecule, termed FXII900, efficiently blocks FXIIa in mice, rabbits, and pigs. We found that it reduces ferricchloride-induced experimental thrombosis in mice and suppresses blood coagulation in an extracorporeal membrane oxygenation (ECMO) setting in rabbits, all without increasing the bleeding risk. This shows that FXIIa activity is controllable in vivo with a synthetic inhibitor, and that the inhibitor FXII900 is a promising candidate for safe thromboprotection in acute medical conditions.

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“…In this manner the excited state solute molecule significantly changes in photochemistry and photophysics process. The photophysics properties of fluorescent dye has been playing a field of continuous attention since for improved considerate of the excited state molecular properties help not only in designing novel molecules but similarly in improving the performance of these as laser dyes, probes for polymers [1], micellar and in biological systems [2], molecular devices, photovoltaic cells [3], in dielectric enrichment [4], etc. The photophysical properties of coumarin dyes are a dynamic field of exploration for their prominence as laser materials.…”

Section: Introductionmentioning

confidence: 99%

Solvent Dependence on Structure and Electronic Properties of 7-(Diethylamino) - 2H -1- Benzopyran-2- one (C-466) Laser Dye

Renuka

Nadaf²,

Sriprakash³

et al. 2018

J Fluoresc

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In this work, we studied influences on the absorption and fluorescence emission spectra of coumarin-4066 (C-466) with different solvent polarity scale. The spectral shifts reflect the effect of the equilibrium solvents association across the energized solute particle, which adjusts inertially as a result of quick charge realignment upon radiative deactivation to the lowest electronic state. The dipole moments of C-466 are determined by employing the Bakhshiev, Kawski-Chamma-Viallet, Lippert-Mataga and McRae relations. The results from all these methods are, excited state dipole moment of C-466 is higher than the ground state dipole moments and which indicates molecule is less polar in the ground state. Theoretical analysis was also carried out by Density Functional theory (DFT and TD -DFT) employing the BECKE-1998 (exchange)/STO-6G basic set in ethanol solvent and in vacuum medium. The HOMO-LUMO, Solvent Accessible Surfaces (SAS) and Molecular Electrostatic Potential (MEP) were analysed to acquire additional knowledge of the molecular arrangement and electronic properties of C-466. These photophysical properties suggest delineation can be mauled for laying out new luminescent tests for various solvents microenvironment.

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Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors

Cited by 43 publications

References 49 publications

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation

Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs

Solvent Dependence on Structure and Electronic Properties of 7-(Diethylamino) - 2H -1- Benzopyran-2- one (C-466) Laser Dye

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