What are covalent drugs?

Most drugs bind their targets through reversible, non-covalent interactions such as hydrogen bonds and hydrophobic contacts. Covalent drugs go one step further: after binding, they form a chemical bond with an amino acid in the target protein.

An old idea, made precise

Some of the oldest medicines are covalent. Aspirin transfers an acetyl group to the cyclooxygenase enzyme, and penicillin acylates bacterial cell-wall enzymes. For years, the pharmaceutical industry avoided deliberately reactive molecules because of toxicity concerns. That changed with targeted covalent inhibitors: molecules that first bind selectively, then react with one specific, poorly conserved residue near the binding site.

Warheads

Sotorasib, approved in 2021, is a landmark: it drugs a KRAS mutant that had been considered “undruggable” for decades by reacting with the mutant cysteine.

Benefits

• Potency and duration. Activity can last until the cell makes new protein, allowing lower or less frequent doses.
• Selectivity. Targeting a rare cysteine can separate closely related proteins.
• Difficult targets. Shallow sites with weak non-covalent binding can still be drugged.

Risks and how they are managed

Reactive groups can bond with off-target proteins, which may cause toxicity or immune reactions. Designers tune warhead reactivity to be as low as possible, check reactivity with glutathione, and profile which proteins the compound labels in cells. Reversible covalent warheads offer a middle ground.

Finding a starting point often begins with a substructure search for compounds that carry a suitable warhead, followed by covalent docking.