Targeted covalent inhibitors and covalent chemical probes have recently been successfully integrated into drug discovery methods, and a series of systematic studies with the application of covalent binders have shown that carefully designed compounds with tailored reactivity can minimize the risk of toxicity. The most widely used strategy today is to start with known high-affinity non-covalent compounds and introduce electrophilic functional groups at positions closest to the target protein nucleophile. To improve target identification and validation at an early stage, scientists have applied electrophilic fragments that can covalently label the target's nucleophilic amino acids (mainly Cys, Lys, Thr, Tyr, Ser, His, and less commonly Glu and Met). Screening of libraries of electrophilic fragments of the proteome of living cells provides important information on ligand properties and the potential druggability of proteins, which can deliver novel targets for drug discovery programs.
Figure 1. Targeting HOIP using fragment-based covalent ligand screening. (Johansson, H.; et al. 2019)
Advantages of the Covalent Mechanism
- Improved potency and selectivity
- Prolonged duration of action
- Beneficial pharmacokinetic (PK) profile
Covalent Libraries Design
- Electrophilic warhead design
Covalent fragments can be derived from their non-covalent precursors by applying appropriate electrophilic functional groups (often referred to as ‘warheads’).
The range of reactivity required for electrophiles and targeted nucleophilic amino acid residues are carefully evaluated.
- Electrophilic fragments design
The reactivity, reversibility, stability, synthetic accessibility and size of the electrophilic functionality are fully considered.
- Electrophilic fragment library design
- Predicting the reactivity of electrophilic fragments
Computational prediction of reactivity of potential library members or calculate molecular indices and reactivity descriptors are applied
Our Services
To make it easier and better for researchers, BOC Sciences has designed a Covalent Library containing multiple compound collections. We have prepared the most convenient services for you.
Covalent Fragment Library
Automated parallel chemistry is utilized for the design and synthesis of new covalent binders. We have carefully selected the latest attractive and highly tractable covalent functionalities to build our Covalent Fragment Library that contains various scaffolds in combination with most interesting covalent anchors.
Specific Covalent Inhibitor Fragment Library
Considering some compounds containing specific reactive moieties such as acrylamide, vinulsulfone, and vinylsulfonamide groups may improve the drug-like properties of potential drug candidates. CD BioScience has designed our proprietary library of specific covalent inhibitor fragments containing compounds with carbon-carbon double bonds activated by carbonyl or sulfo groups.
Figure 2. Design and synthesis of an electrophilic fragment library. (Johansson, H.; et al. 2019)
Boronic Acid Fragments
Boronic acid is able to form a reversible covalent bond with the side chain of serine or threonine in the protein, prior to the highly reactive active site residues found in hydrolases. Screening compounds and fragments containing boron can selectively act on serine residues in the active site of biological targets. We offer a wide variety of organoboron derivatives, from small decorative building blocks to intermediates and complex scaffolds for library synthesis.
Cysteine focused Covalent Fragments
Nowadays, Cys residues have brought new possibilities for the discovery and synthesis of novel covalent modifiers. Our experienced teams use a deep knowledge-based approach combined with attractive scaffolds and well-validated covalent warheads, to design and synthesize our unique Cysteine Focused Fragment Library.
Serine focused Covalent Fragments
Different specific covalent chemical probes are increasingly being used for proteome-wide target identification and imaging, as well as for finding inhibitors with high specificity in related enzymes and enzyme isoforms. Our Serine focused Covalent Fragment Library is designed based on a combination of specific parts.
Lysine focused covalent fragments
Lysine residues are present at the surface and in active sites of many enzymes, as well as ‘hot spots’ of protein-protein interactions. CD BioScience has carefully selected common and specific electrophiles to design our Lysine-focused Covalent Fragment Library.
Electrophilic Covalent Probe Library
Aiming to discover new inhibitors for cysteine-containing proteins, we can construct a library of electrophilic covalent probes to assess the thiol reactivity of all fragments and screen against different cysteine-containing proteins. In addition, overreactive and promiscuous covalent binders have been eliminated from this library.
What We Deliver
- Reliable Covalent Libraries are constructed in different size and design intention
- Comprehensive support in developing your hit compounds
- All compounds have a minimum purity of 90% assessed by 1H NMR
- Analytical data is available
BOC Sciences provides professional, rapid and high-quality services of Covalent Library design at competitive prices for global customers. Personalized and customized services of Covalent Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!
Reference
- Johansson, H.; et al. Fragment-Based Covalent Ligand Screening Enables Rapid Discovery of Inhibitors for the RBR E3 Ubiquitin Ligase HOIP. Journal of the American Chemical Society. 2019. 141(6): 2703-2712.
