{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T13:02:11Z","timestamp":1770469331318,"version":"3.49.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020771","name":"Young Scientists Fund of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62302357"],"award-info":[{"award-number":["62302357"]}],"id":[{"id":"10.13039\/501100020771","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["2023-JC-QN-0707"],"award-info":[{"award-number":["2023-JC-QN-0707"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62172318"],"award-info":[{"award-number":["62172318"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62202353"],"award-info":[{"award-number":["62202353"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62302316"],"award-info":[{"award-number":["62302316"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A2037"],"award-info":[{"award-number":["U22A2037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>The structural complexities enable RNA to serve as a versatile molecular scaffold capable of binding small molecules with high specificity. Understanding these interactions is essential for elucidating RNA\u2019s role in disease mechanisms and developing RNA-targeted therapeutics. However, predicting RNA-small molecule binding sites remains a significant challenge due to their conformational flexibility, structural diversity, and the limited availability of high-resolution structural data.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In this study, we propose RLsite, a novel computational framework integrating pre-trained RNA language models with graph attention networks (GAT) to predict small-molecule binding sites on RNA. Our method effectively captures both sequential and structural features of RNA by leveraging large-scale RNA sequence data to learn intrinsic patterns and processing graph-based RNA structures to highlight key topological and spatial features. Compared to existing methods, RLsite demonstrates superior accuracy, generalizability, and biological relevance, achieving a Precision of 0.749, a Recall of 0.654, an MCC of 0.474, and an AUC of 0.828 on the public test set, which significantly outperforms the previous models, such as CapBind (an AUC of 0.770), MultiModRLBP (an AUC of 0.780), and RNABind (an AUC of 0.471). Notably, a case study of the PreQ1 riboswitch has achieved strong predictive performance (AUC\u2009=\u20090.97, Recall\u2009=\u20090.9), and its predicted binding sites have been confirmed experimentally. These results underscore our method as a potentially powerful tool for RNA-targeted drug discovery and advancing our understanding of RNA-ligand interactions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The resource codes and data can be accessed at https:\/\/github.com\/SaisaiSun\/RLsite.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf447","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T18:30:52Z","timestamp":1755023452000},"source":"Crossref","is-referenced-by-count":3,"title":["RNA language model and graph attention network for RNA and small molecule binding sites prediction"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6090-3030","authenticated-orcid":false,"given":"Saisai","family":"Sun","sequence":"first","affiliation":[{"name":"School of Computer Science and Technology, Xidian University , Xi\u2019an, Shaanxi 710126,","place":["China"]}]},{"given":"Jianyi","family":"Yang","sequence":"additional","affiliation":[{"name":"MOE Frontiers Science Center for Nonlinear Expectations, Research Center for Mathematics and Interdisciplinary Sciences, Shandong University , Qingdao, Shandong 266237,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6396-0787","authenticated-orcid":false,"given":"Lin","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Xidian University , Xi\u2019an, Shaanxi 710126,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5971-046X","authenticated-orcid":false,"given":"Pengyong","family":"Li","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Xidian University , Xi\u2019an, Shaanxi 710126,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0888-6575","authenticated-orcid":false,"given":"Yumeng","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Big Data and Internet, Shenzhen Technology University , Shenzhen, Guangdong 518118,","place":["China"]}]}],"member":"286","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"2025090822121791200_btaf447-B1","doi-asserted-by":"crossref","first-page":"5856","DOI":"10.1038\/s41467-021-25973-x","article-title":"A chemical probe based on the PreQ(1) metabolite enables transcriptome-wide mapping of binding sites","volume":"12","author":"Balaratnam","year":"2021","journal-title":"Nat Commun"},{"key":"2025090822121791200_btaf447-B2","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/s41589-024-01801-3","article-title":"Engineering covalent small molecule-RNA complexes in living cells","volume":"21","author":"Bereiter","year":"2025","journal-title":"Nat Chem Biol"},{"key":"2025090822121791200_btaf447-B3","doi-asserted-by":"crossref","first-page":"D564","DOI":"10.1093\/nar\/gkae1091","article-title":"Updated resources for exploring experimentally-determined PDB structures and computed structure models at the RCSB protein data bank","volume":"53","author":"Burley","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"2025090822121791200_btaf447-B4","author":"Chen","year":"2022"},{"key":"2025090822121791200_btaf447-B5","doi-asserted-by":"crossref","first-page":"16002","DOI":"10.1021\/acs.jmedchem.4c01330","article-title":"RNA-Binding small molecules in drug discovery and delivery: an overview from fundamentals","volume":"67","author":"Chen","year":"2024","journal-title":"J Med Chem"},{"key":"2025090822121791200_btaf447-B6","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/s41573-022-00521-4","article-title":"Targeting RNA structures with small molecules","volume":"21","author":"Childs-Disney","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"2025090822121791200_btaf447-B7","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41576-024-00693-2","article-title":"Targeting and engineering long non-coding RNAs for cancer therapy","volume":"25","author":"Coan","year":"2024","journal-title":"Nat Rev Genet"},{"key":"2025090822121791200_btaf447-B8","doi-asserted-by":"crossref","first-page":"D212","DOI":"10.1093\/nar\/gkaa921","article-title":"RNAcentral 2021: secondary structure integration, improved sequence search and new member databases","volume":"49","author":"Consortium, R.N","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"2025090822121791200_btaf447-B9","doi-asserted-by":"crossref","first-page":"9821","DOI":"10.1093\/nar\/gkad667","article-title":"tRNA queuosine modification is involved in biofilm formation and virulence in bacteria","volume":"51","author":"D\u00edaz-Rullo","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"2025090822121791200_btaf447-B10","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41598-024-83451-y","article-title":"Decoding the general role of tRNA queuosine modification in eukaryotes","volume":"15","author":"D\u00edaz-Rullo","year":"2025","journal-title":"Sci Rep"},{"key":"2025090822121791200_btaf447-B11","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1021\/cb500499x","article-title":"RNA mango aptamer-fluorophore: a bright, high-affinity complex for RNA labeling and tracking","volume":"9","author":"Dolgosheina","year":"2014","journal-title":"ACS Chem Biol"},{"key":"2025090822121791200_btaf447-B12","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41594-018-0062-4","article-title":"High-performance virtual screening by targeting a high-resolution RNA dynamic ensemble","volume":"25","author":"Ganser","year":"2018","journal-title":"Nat Struct Mol Biol"},{"key":"2025090822121791200_btaf447-B13","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1002\/anie.202012330","article-title":"RNA-PROTACs: degraders of RNA-binding proteins","volume":"60","author":"Ghidini","year":"2021","journal-title":"Angew Chem Int Ed Engl"},{"key":"2025090822121791200_btaf447-B14","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.tibs.2004.08.005","article-title":"Aminoacylation of the anticodon stem by a tRNA-synthetase paralog: relic of an ancient code?","volume":"29","author":"Grosjean","year":"2004","journal-title":"Trends Biochem Sci"},{"key":"2025090822121791200_btaf447-B15","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41576-022-00550-0","article-title":"The nexus between RNA-binding proteins and their effectors","volume":"24","author":"He","year":"2023","journal-title":"Nat Rev Genet"},{"key":"2025090822121791200_btaf447-B16","first-page":"4696","article-title":"Relationship of the queuine content of transfer ribonucleic acids to histopathological grading and survival in human lung cancer","volume":"52","author":"Huang","year":"1992","journal-title":"Cancer Res"},{"key":"2025090822121791200_btaf447-B17","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nature11607","article-title":"B12 cofactors directly stabilize an mRNA regulatory switch","volume":"492","author":"Johnson","year":"2012","journal-title":"Nature"},{"key":"2025090822121791200_btaf447-B18","first-page":"1","article-title":"Decoding the interactions and functions of non-coding RNA with artificial intelligence","volume":"9","author":"Jung","year":"2025","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2025090822121791200_btaf447-B19","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: multiple ligand-protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J Chem Inf Model"},{"key":"2025090822121791200_btaf447-B20","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.3390\/ijms19113527","article-title":"Structural studies of the 3',3'-cGAMP riboswitch induced by cognate and noncognate ligands using molecular dynamics simulation","volume":"19","author":"Li","year":"2018","journal-title":"Int J Mol Sci"},{"key":"2025090822121791200_btaf447-B21","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1093\/bib\/bbx165","article-title":"BioSeq-Analysis: a platform for DNA, RNA and protein sequence analysis based on machine learning approaches","volume":"20","author":"Liu","year":"2019","journal-title":"Brief Bioinform"},{"key":"2025090822121791200_btaf447-B22","first-page":"1","article-title":"RNet: a network strategy to predict RNA binding preferences","volume":"25","author":"Liu","year":"2024","journal-title":"Brief Bioinform"},{"key":"2025090822121791200_btaf447-B23","first-page":"e74","article-title":"DSSR-enabled innovative schematics of 3D nucleic acid structures with PyMOL","volume":"48","author":"Lu","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2025090822121791200_btaf447-B24","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1093\/bioinformatics\/btab844","article-title":"RNAglib: a python package for RNA 2.5 D graphs","volume":"38","author":"Mallet","year":"2022","journal-title":"Bioinformatics"},{"key":"2025090822121791200_btaf447-B25","doi-asserted-by":"crossref","first-page":"189","DOI":"10.12688\/f1000research.7931.1","article-title":"FreeSASA: an open source C library for solvent accessible surface area calculations","volume":"5","author":"Mitternacht","year":"2016","journal-title":"F1000Res"},{"key":"2025090822121791200_btaf447-B26","doi-asserted-by":"crossref","first-page":"e202401800","DOI":"10.1002\/chem.202401800","article-title":"Corrin ring modifications reveal the chemical and spatial requirements for the B12-btuB riboswitch interaction","volume":"30","author":"Musiari","year":"2024","journal-title":"Chem Eur J"},{"key":"2025090822121791200_btaf447-B27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41576-023-00662-1","article-title":"Non-coding RNAs in disease: from mechanisms to therapeutics","volume":"25","author":"Nemeth","year":"2024","journal-title":"Nat Rev Genet"},{"key":"2025090822121791200_btaf447-B28","doi-asserted-by":"crossref","first-page":"5725","DOI":"10.1038\/s41467-024-49638-7","article-title":"Identifying small-molecules binding sites in RNA conformational ensembles with SHAMAN","volume":"15","author":"Panei","year":"2024","journal-title":"Nat Commun"},{"key":"2025090822121791200_btaf447-B29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.celrep.2015.03.004","article-title":"Structural basis for molecular discrimination by a 3',3'-cGAMP sensing riboswitch","volume":"11","author":"Ren","year":"2015","journal-title":"Cell Rep"},{"key":"2025090822121791200_btaf447-B30","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1177\/2472555219885373","article-title":"Targeting RNA with small molecules: identification of selective, RNA-binding small molecules occupying Drug-Like chemical space","volume":"25","author":"Rizvi","year":"2020","journal-title":"SLAS Discov"},{"key":"2025090822121791200_btaf447-B31","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1042\/EBC20200011","article-title":"Targeting RNA structures in diseases with small molecules","volume":"64","author":"Shao","year":"2020","journal-title":"Essays Biochem"},{"key":"2025090822121791200_btaf447-B32","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.chembiol.2019.04.012","article-title":"Binding between G quadruplexes at the homodimer interface of the corn RNA aptamer strongly activates thioflavin T fluorescence","volume":"26","author":"Sjekloca","year":"2019","journal-title":"Cell Chem Biol"},{"key":"2025090822121791200_btaf447-B33","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1093\/bioinformatics\/btaa1092","article-title":"Recognition of small molecule-RNA binding sites using RNA sequence and structure","volume":"37","author":"Su","year":"2021","journal-title":"Bioinformatics"},{"key":"2025090822121791200_btaf447-B34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/71253","article-title":"The structural basis for molecular recognition by the vitamin B 12 RNA aptamer","volume":"7","author":"Sussman","year":"2000","journal-title":"Nat Struct Biol"},{"key":"2025090822121791200_btaf447-B35","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/s41589-019-0267-9","article-title":"Structure and functional reselection of the Mango-III fluorogenic RNA aptamer","volume":"15","author":"Trachman","year":"2019","journal-title":"Nat Chem Biol"},{"key":"2025090822121791200_btaf447-B36","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/nchembio.2392","article-title":"Structural basis for high-affinity fluorophore binding and activation by RNA Mango","volume":"13","author":"Trachman","year":"2017","journal-title":"Nat Chem Biol"},{"key":"2025090822121791200_btaf447-B37","author":"Velikovi","year":"2017"},{"key":"2025090822121791200_btaf447-B38","author":"Wang","year":"2025"},{"key":"2025090822121791200_btaf447-B39","doi-asserted-by":"crossref","first-page":"4995","DOI":"10.1109\/JBHI.2024.3400521","article-title":"MultiModRLBP: a deep learning approach for multi-modal RNA-small molecule ligand binding sites prediction","volume":"28","author":"Wang","year":"2024","journal-title":"IEEE J Biomed Health Inform"},{"key":"2025090822121791200_btaf447-B40","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/s42256-024-00836-4","article-title":"Multi-purpose RNA language modelling with motif-aware pretraining and type-guided fine-tuning","volume":"6","author":"Wang","year":"2024","journal-title":"Nat Mach Intell"},{"key":"2025090822121791200_btaf447-B41","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1093\/bioinformatics\/bty345","article-title":"RBind: computational network method to predict RNA binding sites","volume":"34","author":"Wang","year":"2018","journal-title":"Bioinformatics"},{"key":"2025090822121791200_btaf447-B42","first-page":"1","article-title":"RLBind: a deep learning method to predict RNA-ligand binding sites","volume":"24","author":"Wang","year":"2023","journal-title":"Brief Bioinform"},{"key":"2025090822121791200_btaf447-B43","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1093\/nar\/gkad055","article-title":"DeepBIO: an automated and interpretable deep-learning platform for high-throughput biological sequence prediction, functional annotation and visualization analysis","volume":"51","author":"Wang","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"2025090822121791200_btaf447-B44","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1038\/nchembio.2475","article-title":"A homodimer interface without base pairs in an RNA mimic of red fluorescent protein","volume":"13","author":"Warner","year":"2017","journal-title":"Nat Chem Biol"},{"key":"2025090822121791200_btaf447-B45","doi-asserted-by":"crossref","first-page":"107631","DOI":"10.1016\/j.compbiomed.2023.107631","article-title":"ConPep: prediction of peptide contact maps with pre-trained biological language model and multi-view feature extracting strategy","volume":"167","author":"Wei","year":"2023","journal-title":"Comput Biol Med"},{"key":"2025090822121791200_btaf447-B46","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.future.2024.05.029","article-title":"An interpretable deep learning model predicts RNA\u2013small molecule binding sites","volume":"159","author":"Xi","year":"2024","journal-title":"Fut Gener Comput. Syst"},{"key":"2025090822121791200_btaf447-B47","doi-asserted-by":"publisher","author":"Yin","year":"2024","DOI":"10.1101\/2024.03.17.585376"},{"key":"2025090822121791200_btaf447-B48","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1124\/pr.120.019554","article-title":"RNA drugs and RNA targets for small molecules: principles, progress, and challenges","volume":"72","author":"Yu","year":"2020","journal-title":"Pharmacol Rev"},{"key":"2025090822121791200_btaf447-B49","doi-asserted-by":"crossref","first-page":"19016","DOI":"10.1038\/srep19016","article-title":"Rsite2: an efficient computational method to predict the functional sites of noncoding RNAs","volume":"6","author":"Zeng","year":"2016","journal-title":"Sci Rep"},{"key":"2025090822121791200_btaf447-B50","doi-asserted-by":"crossref","first-page":"9179","DOI":"10.1038\/srep09179","article-title":"Rsite: a computational method to identify the functional sites of noncoding RNAs","volume":"5","author":"Zeng","year":"2015","journal-title":"Sci Rep"},{"key":"2025090822121791200_btaf447-B51","doi-asserted-by":"crossref","first-page":"100794","DOI":"10.1016\/j.xcrm.2022.100794","article-title":"Deep generative molecular design reshapes drug discovery","volume":"3","author":"Zeng","year":"2022","journal-title":"Cell Rep Med"},{"key":"2025090822121791200_btaf447-B52","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1093\/nar\/gkad1031","article-title":"Multiple sequence alignment-based RNA language model and its application to structural inference","volume":"52","author":"Zhang","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"2025090822121791200_btaf447-B53","doi-asserted-by":"crossref","first-page":"169010","DOI":"10.1016\/j.jmb.2025.169010","article-title":"Identifying RNA-small molecule binding sites using geometric deep learning with language models","volume":"437","author":"Zhu","year":"2025","journal-title":"J Mol Biol"},{"key":"2025090822121791200_btaf447-B54","doi-asserted-by":"crossref","first-page":"104","DOI":"10.3390\/life15010104","article-title":"Advances and mechanisms of RNA-Ligand interaction predictions","volume":"15","author":"Zhuo","year":"2025","journal-title":"Life"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaf447\/63969674\/btaf447.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/9\/btaf447\/63969674\/btaf447.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/9\/btaf447\/63969674\/btaf447.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T02:13:57Z","timestamp":1757384037000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btaf447\/8223477"}},"subtitle":[],"editor":[{"given":"Jianlin","family":"Cheng","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":54,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaf447","relation":{},"ISSN":["1367-4811"],"issn-type":[{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,8,6]]},"article-number":"btaf447"}}