{"doi":"10.1039/d2md00112h","title":"Recent applications of covalent chemistries in protein–protein interaction inhibitors","abstract":"Protein-protein interactions (PPIs) are large, often featureless domains whose modulations by small-molecules are challenging. Whilst there are some notable successes, such as the BCL-2 inhibitor venetoclax, the requirement for larger ligands to achieve the desired level of potency and selectivity may result in poor \"drug-like\" properties. Covalent chemistry is presently enjoying a renaissance. In particular, targeted covalent inhibition (TCI), in which a weakly electrophilic \"warhead\" is installed onto a protein ligand scaffold, is a powerful strategy to develop potent inhibitors of PPIs that are smaller/more drug-like yet have enhanced affinities by virtue of the reinforcing effect on the existing non-covalent interactions by the resulting protein-ligand covalent bond. Furthermore, the covalent bond delivers sustained inhibition, which may translate into significantly reduced therapeutic dosing. Herein, we discuss recent applications of a spectrum of TCIs, as well as covalent screening strategies, in the discovery of more effective inhibitors of PPIs using the HDM2 and BCL-2 protein families as case studies.","journal":"RSC Medicinal Chemistry","year":2022,"id":269699,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":932467,"name":"Christopher C. Goodis","orcid":null,"position":1,"is_corresponding":false},{"id":933380,"name":"Elie G. Pommier","orcid":null,"position":2,"is_corresponding":false},{"id":420254,"name":"Steven Fletcher","orcid":"0000-0002-4429-8334","position":3,"is_corresponding":false},{"id":428276,"name":"Alexandria M. Chan","orcid":"0000-0001-6196-3036","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:27:22.602796Z","pmid":"36092144","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}