Covalent lysine binder library

Covalent lysine binder library 

The use of covalently binding inhibitors is steadily growing, with numerous molecules progressing through the stages of clinical trials and even make it to become marketed drugs [1]. Currently cysteine (Cys) and Serine (Ser) are the most abundantly used residue to target convalently bound inhibitors [2], since they have the most nucleophilic side chain thiolate and alcoholate groups, feasible at physiological conditions. However, cysteine is relatively scarcely represented in protein sequences in general and at protein surfaces in particular. Non catalytic serine in turn is less readily deprotonated. Therefore additional efforts are currently undertaken to study options for selective binding to other side chains. Lysine is far more abundant in proteins binding sites than cysteine, thus it is considered as one of the promising target for rational design of targeted covalent inhibitors (TCI) [1]. The main obstacle is that lysine is less nucleophilic and moreover is usually protonated at physiological conditions. However, significant changes in pKa of Lys residues were reported [3] depending on the Lys residue environment, which potentially opens the way to increase chances of productive and targeted covalent binding.

In this library the structures containing the electrophilic warheads preferentially binding to Lys are gathered for subsequent use in early stages of drug discovery. The most comprehensive and reliable source of such warhead patterns by the time [4] was used to filter ChemDiv’s stock compounds. Additionally, MedChem filters were applied to the structures to ensure their drug-like properties.

1. Singh, J. (2022). The ascension of targeted covalent inhibitors. Journal of Medicinal Chemistry, 65(8), 5886-5901.

2. Lonsdale, R., & Ward, R. A. (2018). Structure-based design of targeted covalent inhibitors. Chemical Society Reviews, 47(11), 3816-3830.

3. Ishikita, H. (2010). Origin of the pKa shift of the catalytic lysine in acetoacetate decarboxylase. FEBS letters, 584(15), 3464-3468.

4. Abbasov, M. E., Kavanagh, M. E., Ichu, T. A., Lazear, M. R., Tao, Y., Crowley, V. M., ... & Cravatt, B. F. (2021). A proteome-wide atlas of lysine-reactive chemistry. Nature chemistry, 13(11), 1081-1092.