Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

Abstract

Some of the most widely used drugs, such as aspirin and penicillin, are covalent drugs. Covalent binding can improve potency, selectivity, and duration of the effects, but the intrinsic reactivity represents a potential liability and may result in idiosyncratic toxicity. For decades, the cons were believed to outweigh the pros, and covalent targeting was deprioritized in drug discovery. Recently, several covalent inhibitors have been approved for cancer treatment, thus rebooting the field. In this review, we briefly reflect on the history of selective covalent targeting, and provide a comprehensive overview of emerging developments from a chemical biology stand-point. Our discussion will reflect on efforts to validate irreversible covalent ligands, expand the scope of targets, and discover new ligands and warheads. We conclude with a brief commentary of remaining limitations and emerging opportunities in selective covalent targeting.

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

“…Rationally designed covalent drugs are gaining traction, with many recent FDA approvals 55,56 . Their design is based on very potent non-covalent binding, that allows precise orientation of a low reactivity electrophile, so that formation of the covalent bond is reliant on binding site specificity, with minimal off-target effects [57][58][59] . For fear of over-reactivity, covalent inhibitors are expunged from high-throughput screening libraries and are typically considered as PAINS compounds [60][61][62] .…”

Transcriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity

“…Specifically, it is a member of an emerging class of kinase inhibitor drugs that bind their targets covalently (type VI KIs). These drugs are highly underrepresented in the databases used in this analysis, explaining the misclassification of ibrutinib 30 .…”

The European Federation for Medicinal Chemistry (EFMC) Best Practice Initiative: Validating Chemical Probes

“…[13] Importantly, a compound that contains a structural alert can still be a good probe, for example, many covalent inhibitors containing reactive functional groups are highly specific to their target. [14,15] A structural alert is simply a flag that should lead to more careful data interpretation and more thorough validation of the probe as the risk of false-positive activity in an assay increases. In addition to the structure check, compound and sample properties are critical to characterize to validate a probe.…”