Description: Recently, significant advancements in tyrosine-targeting electrophiles have primarily occurred in the field of protein-protein interactions (PPIs), where cysteine residues are often underrepresented and novel chemistries are needed to address these interfaces. In this context, tyrosines are frequently more accessible compared to more buried binding sites. Moreover, they are commonly found at "hot spots," which are functional epitopes of PPIs, with 12.3% of the residues consisting of tyrosines. This prevalence is likely due to the hydrophobic nature of tyrosine, its ability to participate in aromatic π-interactions, and its capacity for hydrogen bonding. Beyond PPIs, some progress has also been made in covalent tyrosine targeting in other areas where more commonly addressed side chains are lacking. Even though tyrosine has a slightly lower pKa value compared to the protonated lysine side chain (approximately 10 vs. 10.5 for the unprotected amino acid side chains), significantly less progress has been made in the development of tyrosine-targeted covalent ligands compared to lysine. This is likely due to the reduced flexibility of the tyrosine side chain and the greater steric hindrance of its hydroxy group, which makes it more challenging to adopt suitable reaction geometries.
Recently, significant advancements in tyrosine-targeting electrophiles have primarily occurred in the field of protein-protein interactions (PPIs), where cysteine residues are often underrepresented and novel chemistries are needed to address these interfaces. In this context, tyrosines are frequently more accessible compared to more buried binding sites. Moreover, they are commonly found at "hot spots," which are functional epitopes of PPIs, with 12.3% of the residues consisting of tyrosines. This prevalence is likely due to the hydrophobic nature of tyrosine, its ability to participate in aromatic π-interactions, and its capacity for hydrogen bonding. Beyond PPIs, some progress has also been made in covalent tyrosine targeting in other areas where more commonly addressed side chains are lacking. Even though tyrosine has a slightly lower pKa value compared to the protonated lysine side chain (approximately 10 vs. 10.5 for the unprotected amino acid side chains), significantly less progress has been made in the development of tyrosine-targeted covalent ligands compared to lysine. This is likely due to the reduced flexibility of the tyrosine side chain and the greater steric hindrance of its hydroxy group, which makes it more challenging to adopt suitable reaction geometries.
Through careful selection, we constructed a structural filter containing over 110 electrophilic groups. By analyzing the electrophilic fragments selected by the structural filter, we removed any molecules with trivial or undesirable structural features. Ultimately, we obtained 124 fragment molecules which can target tyrosine residue and can be used for fragment-based covalent drug discovery.
Advantages:
- A unique collection of 124 fragments that show covalent binding with tyrosine.
- Careful selection of warheads: only those with experimentally validated reactivity are chosen, avoiding over-reactive warheads and any alternative reactive functionalities.
- A useful tool for the fragment-based approach to drug discovery (FBDD).
- All compounds are available off the shelf.
- LCMS or NMR validated to ensure high purity and quality.
Formulation: This fragment library containing 124 fragments with warheads targeting tyrosine residue.
Layout: 96-well storage tube or 96-well plate: 1st and 12th column are left empty. 384-well plate: the first two columns and the last two columns are left empty. Compounds with different concentrations or dissolved in different solvents will be put on separate plates. This way of layout may increase the number of plates because there could be three solvents and three concentrations. If you have other requirements, please let us know.
Container: 96- or 384-well Plate with Peelable Foil Seal; 96-well Format Sample Storage Tube With Screw Cap and Optional 2D Barcode.
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