Lysine focused Covalent Fragments

As an effective method to circumvent acquired drug resistance in oncology, targeted covalent inhibitors have received extensive attention in drug discovery. This strategy utilizes small molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Compared with covalent inhibitors that modify cysteine or serine residues, covalent inhibitors that target the side chain of lysine have attracted less attention. However, targeting nucleophilic lysine residues can also represent a feasible approach for irreversible inhibition. Lysine residues are found at the surface and inactive sites of a diversity of enzymes (such as some kinases, viral polymerases and integrases, aldolases, DOPA decarboxylase, P-glycoprotein), as well as in the ‘hot spots’ of protein-protein interactions.

BOC Sciences is able to construct a Lysine focused Covalent Fragment Library based on specific structure moieties. Moreover, our library is available in multiple pre-plated formats for most convenient and fast delivery according to your specific requirement.

Figure 1. Lysine-Targeting Covalent Inhibitors. (Pettinger, J.; et al. 2017)

Library Design

Lysine Targeted Covalent Inhibitor Design

Rational design of lysine-targeted covalent inhibitors is usually challenging due to the availability of carefully selected compound libraries. In addition, fragment-based methods is a useful strategy for developing covalent inhibitors that target lysine residues. BOC Sciences chemists have created a Lysine focused Covalent Fragment Library consist of 1,600 high-quality fragments, which can be a powerful tool for exploring this field. Here are the main steps for lysine-targeting inhibitor design:

• A series of common electrophiles and more specific electrophiles for lysine residues are applied for substructure searches to include compounds in the library
• The further selection process includes filtering through physicochemical parameters based on the extended Rule of Three
• Finally, we remove the trivial chemical types and perform a careful visual inspection

Advanced Covalent Warhead

Table1. The summary of the BOC Sciences Lysine focused Covalent Fragment Library characteristics

Features of Lysine focused Covalent Fragments

• Multiple filtering criteria (physical and chemical filters) are applied to BOC Sciences General Fragment Library to produce a top-level Lysine focused Covalent Fragment Library
• Each undesirable function is removed successfully by using PAINS and our in-house developed reactivity filters
• Our experienced chemists carefully select the covalent warheads based on their reactivity
• All fragments are synthesized with most reliable covalent warheads with well determined reactivity
• All compounds with side functional groups that interfere under most of the reaction conditions have been successfully removed from our library
• Cherry-picking is available

What We Deliver

• Deliver our library in any convenient for your project formats
• Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
• All compounds pass QC evaluation (purity above 90%) before formatting to ensure the quality of the library by ¹H NMR
• Spectral data is available

BOC Sciences provides professional, rapid and high-quality services of Lysine focused Covalent Fragments design at competitive prices for global customers. Personalized and customized services of Lysine focused Covalent Fragments 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!