{"doi":"10.1021/acs.jmedchem.6b01815","title":"Determining Cysteines Available for Covalent Inhibition Across the Human Kinome","abstract":"Covalently bound protein kinase inhibitors have been frequently designed to target noncatalytic cysteines at the ATP binding site. Thus, it is important to know if a given cysteine can form a covalent bond. Here we combine a function-site interaction fingerprint method and DFT calculations to determine the potential of cysteines to form a covalent interaction with an inhibitor. By harnessing the human structural kinome, a comprehensive structure-based binding site cysteine data set was assembled. The orientation of the cysteine thiol group indicates which cysteines can potentially form covalent bonds. These covalent inhibitor easy-available cysteines are located within five regions: P-loop, roof of pocket, front pocket, catalytic-2 of the catalytic loop, and DFG-3 close to the DFG peptide. In an independent test set these cysteines covered 95% of covalent kinase inhibitors. This study provides new insights into cysteine reactivity and preference which is important for the prospective development of covalent kinase inhibitors.","journal":"Journal of Medicinal Chemistry","year":2017,"id":992,"datarank":0.7193685818395114,"base_score":4.795790545596741,"endowment":4.795790545596741,"self_citation_contribution":0.7193685818395114,"citation_network_contribution":0.0,"self_endowment_contribution":0.7193685818395114,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":120,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0486,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2017-04-04","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":12931,"name":"Qingsong Liu","orcid":"0000-0002-7829-2547","position":1,"is_corresponding":false},{"id":5440,"name":"Spencer E. Bliven","orcid":"0000-0002-1200-1698","position":2,"is_corresponding":false},{"id":150,"name":"Lei Xie","orcid":"0000-0001-9051-2111","position":3,"is_corresponding":false},{"id":125,"name":"Philip  E. Bourne","orcid":"0000-0002-7618-7292","position":4,"is_corresponding":false},{"id":293,"name":"Zheng Zhao","orcid":"0000-0003-1453-3230","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"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":[]}