Turning reactivity into selectivity: the challenges, potential and methodology behind covalent screening
Covalent drugs are transitioning from being seen as high risk to an essential strategy in modern small molecule drug discovery. With multiple FDA-approved covalent therapies now on the market, including both KRAS inhibitors, covalent compounds are proving their value against some of the most challenging targets.
Unlike traditional screening, covalent compound discovery hinges on more than transient binding. It requires precise interplay between non-covalent recognition and bond formation, opening the door to targets once considered “undruggable.” Protein–protein interactions, shallow binding pockets, and resistance mutations are just a few areas where covalent strategies can succeed where others fail.
The rewards, however, demand careful execution. Effective covalent compound screening depends on specialized chemistry, rigorous assay design, detailed kinetic analysis (kinact /KI), and robust structural validation to ensure hits are real, selective, and mechanistically sound. When done well, this approach not only improves hit quality but also expands the chemical space available to drug hunters.
This guide highlights the opportunities and challenges behind covalent compound screening and explains why it is gaining momentum across small-molecule discovery.
Download now to explore how covalent strategies can unlock new possibilities for difficult drug targets.
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