Electrophilic Covalent Probe Library

Targeted covalent inhibitor (TCI) has become a useful tool to block protein kinases involved in the pathology of different diseases. Although a diversity of computational protocols have been published for identifying druggable cysteines, the experimental methods used to map the reactivity and accessibility of these residues are limited. TCIs are composed of two main parts: In addition to non-covalent drug-like scaffold, they are also equipped with appropriate electrophilic warheads. In addition to optimizing non-covalent interactions, the rational design of the warhead part is also vital.

BOC Sciences screen this probe kit against multiple kinases that could experimentally characterize the accessibility and reactivity of the targeted cysteines and identify suitable warheads for discovering covalent inhibitors of cysteine-containing proteins.

Library Design

We firstly build a set of fragments that are suitable for evaluating targeted cysteine by performing protein-level biochemical assays
Focusing on covalent interactions, we keep non-covalent parts small and non-polar to minimize the contribution of non-covalent interactions to fragment binding
The covalent fragments we chose represent fragments of different sizes and complexity
In addition, the flexibility of the warhead also varies greatly, depending on the double or triple bond, the direct C-C connection or the binding through an amide bond or a methylene group to the aromatic ring

Library Characterization

Our experts conduct the evaluation of the electrophilic properties of the probe: The local electrophilic index is calculated and these data indicate that our well-designed library covers a wide range of theoretical electrophilicity
For the experimental confirmation, we also test the probe library by employing a GSH-reactivity assay
BOC Sciences has introduced an advanced oligopeptide assay to confirm the cysteine selectivity of the applied covalent fragments

Figure 1. Covalent binding assay. (László, A.; et al. 2020)

Electrophilic Covalent Probe Library Characteristics

BOC Sciences can synthesize a Electrophilic Covalent Probe Library containing more than 900 novel covalent binders. We carefully evaluate the thiol-reactivity of all fragments and screen against 10 cysteine-containing proteins. The acquired knowledge on stability and selectivity has applied to the design of our unique Electrophilic Covalent Probe Library. We cooperate with numerous leading experts in the field of FBDD to design and supply top-level fragment libraries, aiming to meet different requirement of each client.

Table1. The summary of the BOC Sciences Electrophilic Covalent Probe Library characteristics

Parameter	Value
MW	150-550
Number of Rotatable Bonds	≤5
Number of H Donors	≤3
Number of H Acceptors	≤3
TPSA	≤95
Compounds with 'undesirable' functionalities	Removed
CLogP	≤4
Fsp3	<1

Features of Electrophilic Covalent Probe Library

A wide range of chemical structure dissimilarity and are compliant with in-house PAINS structural filters
All compounds are filtered according to the well-known Rule of Three
Choose warheads carefully: only experimentally confirmed reactivity, reported in the literature
Accurate experimental evaluation
No excessive reactivity and miscellaneous covalent binders
Initial SAR data based on small clusters
Easy for quick follow-up
All compounds can be used for cherry-picking

What We Deliver

Delivered within 2 weeks only in any customer-preferred format
Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
All compounds have a minimum purity of 90% assessed by ¹H NMR
Analytical data is provided

BOC Sciences provides professional, rapid and high-quality services of Electrophilic Covalent Probe Library design at competitive prices for global customers. Personalized and customized services of Electrophilic Covalent Probe 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

László, A.; et al. An electrophilic warhead library for mapping the reactivity and accessibility of tractable cysteines in protein kinases. European Journal of Medicinal Chemistry. 2020. 207: 112836.

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Services Based on the Chemical Library Design Platform

BOC Sciences has rich experience in working with global customers in custom library synthesis of compounds and generating small to medium-sized libraries of target compounds. Our knowledge in generating a large number of target molecules in a remarkably shorter time enables quick biological screenings for affinities. With the target properties in mind, we deliver target molecules, by applying our extensive knowledge in drug discovery.

Our mission is to provide clients with a professional chemical library design platform. Empowered by high-quality services and effective research solutions, we are committed to helping customers achieve effective and successful research goals.