{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:35:04Z","timestamp":1784374504891,"version":"3.55.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2018,7,17]],"date-time":"2018-07-17T00:00:00Z","timestamp":1531785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["HG008424"],"award-info":[{"award-number":["HG008424"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["GM117325"],"award-info":[{"award-number":["GM117325"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["GM117080"],"award-info":[{"award-number":["GM117080"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012737","name":"Department of Health and Human Services","doi-asserted-by":"publisher","award":["HHSN272201200026C"],"award-info":[{"award-number":["HHSN272201200026C"]}],"id":[{"id":"10.13039\/100012737","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012737","name":"Department of Health and Human Services","doi-asserted-by":"publisher","award":["HHSN272201700060C"],"award-info":[{"award-number":["HHSN272201700060C"]}],"id":[{"id":"10.13039\/100012737","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PUT Institute of Computing Science Statutory Funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>The correct identification of ligands in crystal structures of protein complexes is the cornerstone of structure-guided drug design. However, cognitive bias can sometimes mislead investigators into modeling fictitious compounds without solid support from the electron density maps. Ligand identification can be aided by automatic methods, but existing approaches are based on time-consuming iterative fitting.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Here we report a new machine learning algorithm called CheckMyBlob that identifies ligands from experimental electron density maps. In benchmark tests on portfolios of up to 219 931 ligand binding sites containing the 200 most popular ligands found in the Protein Data Bank, CheckMyBlob markedly outperforms the existing automatic methods for ligand identification, in some cases doubling the recognition rates, while requiring significantly less time. Our work shows that machine learning can improve the automation of structure modeling and significantly accelerate the drug screening process of macromolecule-ligand complexes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Code and data are available on GitHub at https:\/\/github.com\/dabrze\/CheckMyBlob.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty626","type":"journal-article","created":{"date-parts":[[2018,7,14]],"date-time":"2018-07-14T17:43:43Z","timestamp":1531590223000},"page":"452-461","source":"Crossref","is-referenced-by-count":36,"title":["Automatic recognition of ligands in electron density by machine learning"],"prefix":"10.1093","volume":"35","author":[{"given":"Marcin","family":"Kowiel","sequence":"first","affiliation":[{"name":"Center for Biocrystallographic Research, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland"},{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dariusz","family":"Brzezinski","sequence":"additional","affiliation":[{"name":"Institute of Computing Science, Poznan University of Technology, Poznan, Poland"},{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemyslaw J","family":"Porebski","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID), University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan G","family":"Shabalin","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID), University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz","family":"Jaskolski","sequence":"additional","affiliation":[{"name":"Center for Biocrystallographic Research, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland"},{"name":"Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wladek","family":"Minor","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID), University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,7,17]]},"reference":[{"key":"2023013107240285000_bty626-B1","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1107\/S0907444902016657","article-title":"PHENIX: building new software for automated crystallographic structure determination","volume":"58","author":"Adams","year":"2002","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B2","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.str.2016.02.017","article-title":"Outcome of the first wwPDB\/CCDC\/D3R ligand validation workshop","volume":"24","author":"Adams","year":"2016","journal-title":"Structure"},{"key":"2023013107240285000_bty626-B3","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1107\/S0907444905023152","article-title":"Automated crystallographic ligand building using the medial axis transform of an electron-density isosurface","volume":"61","author":"Aishima","year":"2005","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B4","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2023013107240285000_bty626-B5","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.febslet.2012.12.029","article-title":"Trendspotting in the Protein Data Bank","volume":"587","author":"Berman","year":"2013","journal-title":"FEBS Lett."},{"key":"2023013107240285000_bty626-B6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"2023013107240285000_bty626-B7","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1107\/S1399004714008578","article-title":"Automated identification of crystallographic ligands using sparse-density representations","volume":"70","author":"Carolan","year":"2014","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B8","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1107\/S0907444906022116","article-title":"The Buccaneer software for automated model building. 1. Tracing protein chains","volume":"62","author":"Cowtan","year":"2006","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B9","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1107\/S0907444912000200","article-title":"Handling ligands with Coot","volume":"68","author":"Debreczeni","year":"2012","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B10","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1162\/089976698300017197","article-title":"Approximate statistical tests for comparing supervised classification learning algorithms","volume":"10","author":"Dietterich","year":"1998","journal-title":"Neural Comput."},{"key":"2023013107240285000_bty626-B11","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1107\/S0907444906023389","article-title":"Assessment of automatic ligand building in ARP\/wARP","volume":"63","author":"Evrard","year":"2007","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B12","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1109\/TPAMI.2006.79","article-title":"One-shot learning of object categories","volume":"28","author":"Fei-Fei","year":"2006","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell."},{"key":"2023013107240285000_bty626-B13","first-page":"477","article-title":"Discriminatory analysis, nonparametric discrimination: consistency properties","volume-title":"US Air Force School of Aviation Medicine Technical Report 4","author":"Fix","year":"1951"},{"key":"2023013107240285000_bty626-B14","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1214\/aos\/1013203451","article-title":"Greedy function approximation: a gradient boosting machine","volume":"29","author":"Friedman","year":"2001","journal-title":"Ann. Stat."},{"key":"2023013107240285000_bty626-B15","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-3-642-04031-3_12","article-title":"Ligand electron density shape recognition using 3D zernike descriptors","volume-title":"Pattern Recognition in Bioinformatics","author":"Gunasekaran","year":"2009"},{"key":"2023013107240285000_bty626-B16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1023\/A:1012487302797","article-title":"Gene selection for cancer classification using support vector machines","volume":"46","author":"Guyon","year":"2002","journal-title":"Mach. Learn."},{"key":"2023013107240285000_bty626-B17","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1098\/rsif.2010.0297","article-title":"A moment invariant for evaluating the chirality of three-dimensional objects","volume":"8","author":"Hattne","year":"2011","journal-title":"J. R. Soc. Interface"},{"key":"2023013107240285000_bty626-B18","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1107\/S0021889809008784","article-title":"PDB_REDO: automated re-refinement of X-ray structure models in the PDB","volume":"42","author":"Joosten","year":"2009","journal-title":"J. Appl. Crystallogr."},{"key":"2023013107240285000_bty626-B19","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511921803","volume-title":"Evaluating Learning Algorithms: A Classification Perspective","author":"Japkowicz","year":"(2011)"},{"key":"2023013107240285000_bty626-B20","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/978-1-4899-7687-1_192","article-title":"Curse of dimensionality","volume-title":"Encyclopedia of Machine Learning and Data Mining","author":"Keogh","year":"(2017)"},{"key":"2023013107240285000_bty626-B21","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1107\/S0907444906022657","article-title":"Crystallographic refinement of ligand complexes","volume":"63","author":"Kleywegt","year":"2007","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B22","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1107\/S0907444913000565","article-title":"Visual automated macromolecular model building","volume":"69","author":"Langer","year":"2013","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B23","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature14539","article-title":"Deep learning","volume":"521","author":"LeCun","year":"2015","journal-title":"Nature"},{"key":"2023013107240285000_bty626-B24","doi-asserted-by":"crossref","first-page":"3:1","DOI":"10.1145\/2133360.2133363","article-title":"Isolation-based anomaly detection","volume":"6","author":"Liu","year":"2012","journal-title":"ACM Trans. Knowl. Discov. Data"},{"key":"2023013107240285000_bty626-B25","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1107\/S0907444906019949","article-title":"HKL-3000: the integration of data reduction and structure solution - from diffraction images to an initial model in minutes","volume":"62","author":"Minor","year":"2006","journal-title":"Acta Crystallogr. D Biol. Crystallogr"},{"key":"2023013107240285000_bty626-B26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1107\/S0907444911001314","article-title":"REFMAC5 for the refinement of macromolecular crystal structures","volume":"67","author":"Murshudov","year":"2011","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B27","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1145\/781606.781639","article-title":"3D zernike descriptors for content based shape retrieval","volume-title":"Proc. Eighth ACM Symp. Solid Model. Appl.","author":"Novotni","year":"(2003)"},{"key":"2023013107240285000_bty626-B28","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1107\/S0907444901003894","article-title":"X-LIGAND: an application for the automated addition of flexible ligands into electron density","volume":"57","author":"Oldfield","year":"2001","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B29","first-page":"2825","article-title":"Scikit-learn: machine learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn. Res."},{"key":"2023013107240285000_bty626-B30","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/8263","article-title":"Automated protein model building combined with iterative structure refinement","volume":"6","author":"Perrakis","year":"1999","journal-title":"Nat. Struct. Biol."},{"key":"2023013107240285000_bty626-B31","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/pro.3272","article-title":"Molstack-interactive visualization tool for presentation, interpretation, and validation of macromolecules and electron density maps","volume":"27","author":"Porebski","year":"2018","journal-title":"Protein Sci."},{"key":"2023013107240285000_bty626-B32","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1107\/S0907444912044423","article-title":"Techniques, tools and best practices for ligand electron-density analysis and results from their application to deposited crystal structures","volume":"69","author":"Pozharski","year":"2013","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B33","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1107\/S0108767390000277","article-title":"Phase annealing in SHELX-90: direct methods for larger structures","volume":"46","author":"Sheldrick","year":"1990","journal-title":"Acta Crystallogr. A Found. Crystallogr."},{"key":"2023013107240285000_bty626-B34","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.1093\/bioinformatics\/btm503","article-title":"Moment invariants as shape recognition technique for comparing protein binding sites","volume":"23","author":"Sommer","year":"2007","journal-title":"Bioinformatics"},{"key":"2023013107240285000_bty626-B35","volume-title":"Introduction to Data Mining","author":"Tan","year":"2005)"},{"key":"2023013107240285000_bty626-B36","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/S0076-6879(03)74002-6","article-title":"Solve and resolve: automated structure solution and density modification","volume":"374","author":"Terwilliger","year":"2003","journal-title":"Methods Enzymol."},{"key":"2023013107240285000_bty626-B37","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1107\/S0907444906017161","article-title":"Automated ligand fitting by core-fragment fitting and extension into density","volume":"62","author":"Terwilliger","year":"2006","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B38","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1107\/S0907444906046233","article-title":"Ligand identification using electron-density map correlations","volume":"63","author":"Terwilliger","year":"2007","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B39","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1107\/S0907444910045749","article-title":"Overview of the CCP4 suite and current developments","volume":"67","author":"Winn","year":"2011","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"2023013107240285000_bty626-B40","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0893-6080(05)80023-1","article-title":"Stacked generalization","volume":"5","author":"Wolpert","year":"1992","journal-title":"Neural Netw."},{"key":"2023013107240285000_bty626-B41","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1126\/science.1137128","article-title":"Conformational switching in the fungal light sensor vivid","volume":"316","author":"Zoltowski","year":"2007","journal-title":"Science"},{"key":"2023013107240285000_bty626-B42","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1107\/S0907444904012995","article-title":"Modelling bound ligands in protein crystal structures","volume":"60","author":"Zwart","year":"2004","journal-title":"Acta Crystallogr. D Biol. Crystallogr."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/3\/452\/48964803\/bioinformatics_35_3_452.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/3\/452\/48964803\/bioinformatics_35_3_452.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T10:16:31Z","timestamp":1675160191000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/3\/452\/5055122"}},"subtitle":[],"editor":[{"given":"Robert","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2018,7,17]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019,2,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/bty626","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,2,1]]},"published":{"date-parts":[[2018,7,17]]}}}