covalent ligand

Covalent inhibitors are small molecules that can bind specifically to target proteins through covalent bonds and inhibit their biological functions. Although for a long time, covalent targeting has been playing a subordinate role in drug discovery, with an increasing number of reports on successful clinical applications of such drugs, the potential of these agents is now being acknowledged.

Covalent ligands rely on reactive groups (“warheads”), and new warheads are key to expanding the scope of covalent modalities. 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 8,900 fragment molecules with covalent modification potential, which can target various reactive amino acid residues and can be used for fragment-based covalent drug discovery.

Different functional groups confer unique chemical properties and reactivity characteristics to compounds. The presence of these functional groups not only affects the physical properties of the compounds, such as solubility and boiling point, but also determines their chemical reactivity and potential applications in chemical synthesis.

Covalent ligands rely on reactive groups (“warheads”), and new warheads are key to expanding the scope of covalent modalities. 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 4,900 multifunctional covalent fragments.

Lysine is the second most common target residue used in the design of TCIs and related covalent ligands. Its appeal lies in its abundance in human proteins, which is approximately three times higher than that of cysteine (5.8% vs. 1.9%). This significantly increases the number of proteins suitable for covalent targeting, especially given that many human proteins lack ligandable cysteine residues. Moreover, it has been suggested that functional lysines have a lower probability of being replaced by mutation, as they often play a crucial role in catalysis by acting as bases or nucleophiles. Additionally, lysines are essential for maintaining the structural integrity of proteins and for regulating post-translational modifications (PTMs). Consequently, targeting lysine has garnered significant interest in recent years.

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 445 fragment molecules which can target lysine residue and can be used for fragment-based covalent drug discovery.

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.

MCE Butyl Agarose 4FF is a hydrophobic chromatography medium formed by covalently coupling butyl ligands to agarose. It is suitable for both laboratory use and large-scale industrial purification.

MCE Octyl Agarose 6FF is a hydrophobic chromatography medium formed by covalently coupling butyl ligands to agarose. It is suitable for both laboratory use and large-scale industrial purification.

MCE Phenyl Agarose HP is a high-resolution hydrophobic chromatography medium formed by covalently coupling phenyl ligands to agarose. It is suitable for laboratory-scale and industrial-scale purification of biomolecules.

MCE Butyl Agarose HP is a high-resolution hydrophobic chromatography medium formed by covalently coupling butyl ligands to agarose. It is suitable for both laboratory use and large-scale industrial purification.

MCE Octyl Agarose HP is a high-resolution hydrophobic chromatography medium formed by covalently coupling octyl ligands to agarose. It is suitable for both laboratory use and large-scale industrial purification.

MCE Phenyl Agarose (Low Sub) 6FF is a low-substitution hydrophobic chromatography medium formed by covalently coupling phenyl ligands to agarose. It is suitable for laboratory-scale and industrial-scale purification of biomolecules with relatively weak hydrophobicity.

MCE Phenyl Agarose (High Sub) 6FF is a high-substitution hydrophobic chromatography medium formed by covalently coupling phenyl ligands to agarose. It is suitable for laboratory-scale and industrial-scale purification of biomolecules with relatively weak hydrophobicity.

MCE MBP Agarose (Dextrin) 6FF is prepared by covalently coupling dextrin to an agarose matrix. It features high binding capacity, excellent specificity, and superior ligand stability. It can achieve one-step purification of MBP fusion protein.

MCE SP Agarose HP is a high-resolution strong cation exchanger formed by covalently coupling sulfopropyl (SP) groups to agarose. This medium offers high binding capacity, high specificity, and excellent ligand stability, making it suitable for both laboratory-scale and large-scale industrial purification applications.

MCE DEAE Agarose HP is a high-resolution weak anion exchanger formed by covalently coupling diethylaminoethyl (DEAE) groups to agarose. This medium offers high binding capacity, high specificity, and excellent ligand stability, making it suitable for both laboratory-scale and large-scale industrial purification applications.

MCE Q Agarose HP is a high-resolution strong anion exchanger formed by covalently coupling quaternary ammonium (Q) groups to agarose. This medium offers high binding capacity, high specificity, and excellent ligand stability, making it suitable for both laboratory-scale and large-scale industrial purification applications.

MCE Carboxyl Magnetic beads (200 nm, 10 mg/mL) are characterized by superparamagnetism, fast magnetic response, abundant carboxyl functional groups, monodispersity, and submicron scale particle size. Biological ligands (proteins, peptides, oligonucleotides, drug molecules, etc.) can be covalently coupled to the surface of microspheres under the action of special chemical reagents (such as EDC).

MCE IMAC Agarose (NTA) 6FF is prepared by covalently coupling tetradentate nitrilotriacetic acid (NTA) to an agarose matrix. It features high binding capacity, excellent specificity, and superior ligand stability. The resin allows flexible chelation with metal ions such as Zn²⁺, Ni²⁺, or Cu²⁺, and is suitable for the purification of His-tagged recombinant proteins expressed in bacterial, mammalian, insect, and baculovirus systems.