In recent years, covalent chemical probes have become a hot research topic in drug discovery. The number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has grown significantly; around 30 % of the marketed drugs are covalent binders. This kind of irreversible inhibition has many desirable features, including higher biochemical efficiency of target disruption, lower sensitivity toward pharmacokinetic parameters, and increased duration of action that outlasts the pharmacokinetics of the compound [1]. The design of selective covalent irreversible inhibitors is conceptually very attractive, but in practice hard to achieve. That is because it is challenging to strike the right balance of molecular properties between reactivity and selectivity [2-4].
Taking into account a growing interest and widespread use of fragment-based drug discovery (FBDD), we have designed an exclusive collection of covalent inhibitor fragments based on the Life Chemicals HTS Compound Collection. Initially, all the compounds were filtered according to the Rule of Three criteria. After that, a preliminary set of covalent modifiers was created by singling out compounds with specific structural fragments (functional groups, warheads) [4-8] that are known to form covalent bonds with amino acid residues in binding sites of targeted proteins, e.g., Lys, Cys, Ser, His and Tyr.
The resulting Covalent Fragment Library comprises around 6,500 small-molecule compounds for covalent fragment screening (Fig. 1-2). Focused sets of screening compounds targeting each of the indicated amino acid residues (Cysteine, Lysine, Serine, Histidine, Threonine) can be provided on request.
In addition, we have designed a Diversity Screening Set of 960 covalently binding fragments to provide the most-promising structurally diverse screening compounds in a convenient manner. These covalent fragment-like molecules possess a wide range of chemical structure dissimilarity and are compliant with in-house MedChem and PAINS structural filters [6-7].
The following chemical classes and structural moieties were used for arraying potential covalent inhibitors:
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Each compound within the SD file contains information about the covalent warhead type present in its structure. Additionally, the file named "Covalent Warhead Distribution" contains details regarding the number of compounds belonging to specific functional groups or their combinations.
Figure 1. Distribution of fragments by their covalent warheads in the Covalent Fragment Library
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
For a pre plated set based on this Screening Library, please, go over our Pre-plated Fragment Screening Sets.
Representative compounds from the Covalent Fragment Library
References
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