discovery chemistry
Advancing Next-Generation Covalent Inhibitors
Harnessing Scientific Expertise and Drug-Discovery Experience to Target Complex and Intractable Diseases
Covalent inhibitors offer distinct advantages over traditional reversible inhibitors, including enhanced potency, prolonged target engagement, time-dependent pharmacology and the ability to modulate challenging targets that lack well-defined binding pockets or are driven by transient or shallow binding interactions. When appropriately designed, covalent mechanisms can also enable improved selectivity through controlled reactivity and precise residue targeting.
At o2h discovery, we have capabilities to support the design and development of next-generation covalent inhibitors, spanning both targeted covalent and reversible covalent modalities, with the potential to address complex and previously intractable targets.
Our multidisciplinary teams offer integrated expertise in covalent drug discovery, including informed covalent warhead selection and medicinal chemistry strategies to finely tune intrinsic electrophilicity, steric accessibility, and leaving-group behaviour in order to define the minimum reactivity needed in the warhead and reduce the risk of off-target activity. We have established experimental biology capabilities such as jump-dilution assays to distinguish irreversible from reversible inhibition and to assess the durability of target engagement under enzyme-turnover conditions. In parallel, our ADME team provides the GSH reactivity assay to evaluate intrinsic electrophile reactivity and support early de-risking of off-target liabilities; additionally, the assay has been extended to include GST-mediated conjugation, providing a more physiologically relevant read-out for assessing metabolism-linked reactivity risks.
Through a strong understanding of protein–ligand interactions (including covalent binding geometry and residue microenvironment effects) and modern synthetic capabilities, we seek to deliver tailored solutions that may enhance target engagement and support sustained, mechanism-driven therapeutic effects.
Potential areas of support in covalent inhibitor discovery include:
Identification and optimisation of covalent warheads across multiple electrophile classes
Design and synthesis of selective covalent inhibitors with a focus on balancing potency, selectivity, and reactivity
Support from concept through to preclinical development including hit-to-lead and leadoptimisation phases
Development of residue-specific warheads, targeting cysteine as well as other residues such as lysine, tyrosine, and beyond (including serine and threonine where mechanistically appropriate)
Mechanistic characterisation of covalent binding through kinetic, biochemical, and cellular assays
Early developability assessment encompassing metabolic stability, permeability, and safety-relevant reactivity profiling
Should you wish to discuss how we might support your project, please contact us at [email protected]