CovalentInDB: a comprehensive database facilitating the discovery of covalent inhibitors

Abstract

Inhibitors that form covalent bonds with their targets have traditionally been considered highly adventurous due to their potential off-target effects and toxicity concerns. However, with the clinical validation and approval of many covalent inhibitors during the past decade, design and discovery of novel covalent inhibitors have attracted increasing attention. A large amount of scattered experimental data for covalent inhibitors have been reported, but a resource by integrating the experimental information for covalent inhibitor discovery is still lacking. In this study, we presented Covalent Inhibitor Database (CovalentInDB), the largest online database that provides the structural information and experimental data for covalent inhibitors. CovalentInDB contains 4511 covalent inhibitors (including 68 approved drugs) with 57 different reactive warheads for 280 protein targets. The crystal structures of some of the proteins bound with a covalent inhibitor are provided to visualize the protein–ligand interactions around the binding site. Each covalent inhibitor is annotated with the structure, warhead, experimental bioactivity, physicochemical properties, etc. Moreover, CovalentInDB provides the covalent reaction mechanism and the corresponding experimental verification methods for each inhibitor towards its target. High-quality datasets are downloadable for users to evaluate and develop computational methods for covalent drug design. CovalentInDB is freely accessible at http://cadd.zju.edu.cn/cidb/.

Will the chemical probes please stand up?

“…The targets column counts distinct probe-target annotations. The total number of compounds/targets represents a distinct number of compounds/targets for all sets combined 45 and Chemical Probes Portal, 60 covalent binders from CovalentInDB, 46 and 21 biased GPCR ligands from BiasDB. 19 Our analysis also established that 132 compounds were flagged with one or more structural alerts from either a) PAINS filters, 47,48 b) aggregators, 49 c) cellular assay nuisance compounds 50 or d) historical compounds.…”

“…The full 4466 set includes 275 labelled as drugs (reported to be in clinical phases) with 103 labelled as approved by FDA, EMA and other agencies. The full set also includes 29 PROTACs (Proteolysis Targeting Chimeras) from PROTAC-DB 45 and Chemical Probes Portal, 60 covalent binders from CovalentInDB, 46 and 21 biased GPCR ligands from BiasDB. 19 …”

Will the Chemical Probes Please Stand Up?

“…The full set includes 275 compounds labelled as drugs (defined as compounds in different clinical phases) with 103 labelled as approved (by FDA, EMA and other agencies). The set also includes 29 PROTACs (Proteolysis Targeting Chimeras) from PROTAC-DB 42 and Chemical Probes Portal, 60 covalent binders from CovalentInDB 43 , and 21 biased GPCR ligands from BiasDB 24 .…”

Will the Chemical Probes Please Stand Up?

“…The full 4,466 set includes 275 labelled as drugs (reported to be in clinical phases) with 103 labelled as approved by FDA, EMA and other agencies. The full set also includes 29 PROTACs (Proteolysis Targeting Chimeras) from PROTAC-DB 45 and Chemical Probes Portal, 60 covalent binders from CovalentInDB 46 , and 21 biased GPCR ligands from BiasDB 19 .…”