{"doi":"10.1016/j.csbj.2025.03.003","title":"Kinase-substrate prediction using an autoregressive model","abstract":"Kinase-specific phosphorylation plays a critical role in cellular signaling and various diseases. However, even in model organisms, the substrates of most kinases remain unidentified. Currently, there is no reliable method to predict kinase-substrate relationships. In this study, we introduce an innovative approach leveraging an autoregressive model to predict kinase-substrate pairs. Unlike traditional methods focused on predicting site-specific phosphorylation, our approach addresses kinase-specific protein substrate prediction at the protein level. We redefine this problem as a special type of protein-protein interaction prediction task. Our model integrates protein large language model ESM-2 as the encoder and employs an autoregressive decoder to classify protein-kinase interactions in a binary fashion. We adopted a hard negative strategy, based on kinase embedding distances generated from ESM-2, to compel the model to effectively distinguish positive from negative data. We conducted a top‑k analysis to assess how well our model can prioritize the most likely kinase candidates. Our method is also capable of zero-shot prediction, meaning it can predict substrates for a kinase in case of no known substrates, which cannot be achieved by site-specific prediction methods. Our model's robust generalization to novel kinase and underrepresented groups showcases its versatility and broad utility. Code and data are available at https://github.com/farz1995/substrate_kinase_prediction.","journal":"Computational and Structural Biotechnology Journal","year":2025,"id":533375,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1415599,"name":"Yongfang Qin","orcid":null,"position":1,"is_corresponding":false},{"id":233619,"name":"Duolin Wang","orcid":"0000-0003-1649-460X","position":2,"is_corresponding":false},{"id":233623,"name":"Dong Xu","orcid":"0000-0002-4809-0514","position":3,"is_corresponding":false},{"id":1161158,"name":"Farzaneh Esmaili","orcid":"0000-0002-0002-7305","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:51:32.301795Z","pmid":"40190572","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":[]}