Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa)

Halland, Nis; Czech, Jörg; Czechtizky, Werngard; Evers, Andreas; Follmann, Markus; Kohlmann, Markus; Schreuder, Herman; Kallus, Christopher

doi:10.1021/acs.jmedchem.6b01276

Cited by 10 publications

(13 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IC50 determination (see Table 6) revealed inhibition in the nanomolar range, which is in a similar range compared to other potent small molecule inhibitors of TAFIa that have been reported before. 133,134 In conclusion, this prospective study demonstrates how molecules with large peptidic motifs can be converted into lead-like small molecules with favorable ligand efficiency by shrinking and rescaffolding those regions in the peptidic macrocycle that do not establish key interactions with the target protein. 135 In this publication, several macrocyclic variants of the lead structure have been described that were obtained by structure-based drug design (see selected set of analogues in Table 7).…”

Section: (Figure 3)mentioning

confidence: 82%

Automated Design of Macrocycles for Therapeutic Applications: From Small Molecules to Peptides and Proteins

et al. 2020

Self Cite

View full text Add to dashboard Cite

Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have improved affinity, are able to bind to extended protein interfaces and otherwise have favorable properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive conformation, improve its metabolic stability, cell permeability and in certain cases oral bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the three-dimensional (3D) conformation of the linear molecule in complex with a target protein as starting point, this approach identifies attachment points, generates linkers, evaluates the conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting molecules with respect to their predicted conformational stability and interactions with the target protein. As we show here with several prospective and retrospective case studies, this procedure can be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.The presented approach is an important step towards the enhanced utilization of macrocycles andcyclic peptides as attractive therapeutic modalities. File list (2) download file view on ChemRxiv DesignOfMacrocycles_chemrxiv.pdf (1.85 MiB) download file view on ChemRxiv SUPPORTING INFORMATION.pdf (458.87 KiB)

show abstract

Section: (Figure 3)mentioning

confidence: 82%

Automated Design of Macrocycles for Therapeutic Applications: From Small Molecules to Peptides and Proteins

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Chemical Linkers For Cyclizationmentioning

confidence: 82%

Automated Design of Macrocycles for Therapeutic Applications: from Small Molecules to Peptides and Proteins

Sindhikara¹,

Wagner²,

Gkeka³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

<div>Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have </div><div>improved affinity, are able to bind to extended protein interfaces and otherwise have favorable </div><div>properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive </div><div>conformation, improve its metabolic stability, cell permeability and in certain cases oral </div><div>bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and </div><div>proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the </div><div>three-dimensional (3D) conformation of the linear molecule in complex with a target protein as </div><div>starting point, this approach identifies attachment points, generates linkers, evaluates the </div><div>conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting </div><div>molecules with respect to their predicted conformational stability and interactions with the target </div><div>protein. As we show here with several prospective and retrospective case studies, this procedure can </div><div>be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.</div><div>The presented approach is an important step towards the enhanced utilization of macrocycles and</div><div>cyclic peptides as attractive therapeutic modalities.</div>

show abstract

“…More recently, several novel classes of highly potent TAFIa inhibitors possessing a sulfamide zinc‐binding motif were developed to expand the chemical space [17a,35] . To explore this unusual zinc‐binding motif, many different substituents were employed on R 1 and R 2 as described in scheme 6 [36] . Firstly, conversion of protected amino acid 6.1 to the corresponding N ‐sulfamide oxazolidinones 6.2 using CSI was performed.…”

Section: Methods To Generate Acyclic Sulfamidesmentioning

confidence: 99%

“…[17a,35] To explore this unusual zincbinding motif, many different substituents were employed on R 1 and R 2 as described in scheme 6. [36] Firstly, conversion of protected amino acid 6.1 to the corresponding N-sulfamide oxazolidinones 6.2 using CSI was performed. Treatment with amino acid derivatives 6.4 in refluxing acetonitrile allowed subsequent sulfamide formation to generate the unsymmetric sulfamides 6.5.…”

Section: N-sulfamoyloxazolidinonementioning

confidence: 99%

Implementation of Diverse Synthetic and Strategic Approaches to Biologically Active Sulfamides

Jun

Xie

2021

ChemistrySelect

View full text Add to dashboard Cite

Sulfamide compounds are an important class of motif in various applications in pharmaceutical agents, agriculture, and material science. In this review, various synthetic strategies toward acyclic and cyclic sulfamide compounds utilizing many different methods are described. Herein, efficient and innovative synthetic methods ranging from small molecules to large rings for bioactive compounds, small molecules, and catalyst development are discussed.

show abstract

Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa)

Cited by 10 publications

References 16 publications

Automated Design of Macrocycles for Therapeutic Applications: From Small Molecules to Peptides and Proteins

Automated Design of Macrocycles for Therapeutic Applications: From Small Molecules to Peptides and Proteins

Automated Design of Macrocycles for Therapeutic Applications: from Small Molecules to Peptides and Proteins

Implementation of Diverse Synthetic and Strategic Approaches to Biologically Active Sulfamides

Contact Info

Product

Resources

About