Protein–Peptide Binding Energetics under Crowded Conditions

2020 ◽  
Vol 124 (42) ◽  
pp. 9297-9309
Author(s):  
Samantha S. Stadmiller ◽  
Jhoan S. Aguilar ◽  
Stuart Parnham ◽  
Gary J. Pielak
Keyword(s):  
Peptide Binding ◽  
Binding Energetics

Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

2020 ◽  
Author(s):  
Luke Adams ◽  
Lorna E. Wilkinson-White ◽  
Menachem J. Gunzburg ◽  
Stephen J. Headey ◽  
Martin J. Scanlon ◽  
...  
Keyword(s):  
Binding Site ◽  
Systematic Approach ◽  
Structural Information ◽  
Peptide Binding ◽  
Chemical Diversity ◽  
Chemical Probes ◽  
Protein Targets ◽  
Structure Activity ◽  
Peptide Binding Site ◽  
Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

Barcoded Rational AAV Vector Evolution Enables Systematic In Vivo Mapping of Peptide Binding Motifs

2018 ◽  
Author(s):  
Marcus Davidsson ◽  
Gang Wang ◽  
Patrick Aldrin-Kirk ◽  
Tiago Cardoso ◽  
Sara Nolbrant ◽  
...  
Keyword(s):  
Peptide Binding ◽  
Aav Vector ◽  
Binding Motifs
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