“I’ve worked with ZoBio for more than five years and they have consistently been a trusted partner, bringing deep biophysics expertise and thoughtful structural biology capabilities that have helped move our programs forward, even for some of the most challenging targets we’ve worked on together.”
David Lawson, Vice President of Structural Chemistry, Khartis Therapeutics
Covalent Compound Screening
Discovering hits where conventional screening falls short
Some therapeutic targets remain stubbornly resistant to conventional small molecule discovery. They may lack well-defined binding pockets, present large and flexible protein surfaces, or simply fail to yield meaningful hits from fragment or HTS campaigns.
Covalent screening offers an alternative strategy. By combining carefully designed reactive chemistry with complementary non-covalent interactions, covalent compounds can achieve durable target engagement even when traditional approaches prove unsuccessful.
At ZoBio, we integrate protein science, quantitative biophysics, structural biology and covalent chemistry to identify validated, structurally enabled covalent hits that provide robust starting points for medicinal chemistry.
When should you consider a covalent screening strategy?
Not every target requires a covalent approach. However, covalent screening can provide significant advantages when conventional hit discovery has failed or when the biology demands prolonged target engagement.
Typical situations include:
• Poorly ligandable targets with shallow or flexible binding sites
• Protein-protein interactions
• Targets containing a strategically positioned nucleophilic residue
• Programmes requiring exceptional selectivity
• Projects where long target residence time is expected to improve efficacy
• Follow-up after unsuccessful fragment or HTS campaigns
By exploiting accessible nucleophilic residues such as cysteine, lysine or serine, covalent compounds can convert weak initial recognition into durable, biologically relevant target engagement.
Finding genuine covalent hits
Successful covalent discovery depends on much more than identifying reactive compounds. The challenge is distinguishing genuine mechanism-based binders from non-specific reactivity while ensuring that hits possess the properties required for progression.
Biology-first assay design
Every project begins with high-quality protein and assays designed to report on the desired biological activity rather than chemical reactivity alone. Using orthogonal biophysical techniques, including SPR, we build screening cascades that identify compounds with genuine biological relevance while minimizing false positives.
Characterization that drives medicinal chemistry
Following hit identification, we combine kinetic analysis, intact mass spectrometry and structural biology to establish how compounds engage the target. Quantitative measurements of reversible affinity, covalent bond formation and binding mode provide the mechanistic understanding needed to guide SAR, improve selectivity and accelerate lead optimization.
From validated hits to lead optimization
Covalent hits should not simply be reactive—they should be progressable.
By integrating structural biology, protein science, medicinal chemistry and quantitative biophysics within a single discovery platform, ZoBio delivers structurally enabled hit series supported by clear mechanisms of action and robust kinetic characterization. The result is a strong foundation for efficient design–make–test–analyse cycles and confident progression into lead optimization.
Start a discussion
Whether you are considering covalent chemistry for a challenging target, exploring alternative approaches after conventional screening has failed, or seeking to establish a structure-guided covalent discovery campaign, our scientists can help design the strategy best suited to your programme.