{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:13:01Z","timestamp":1788221581488,"version":"build-2803163510"},"reference-count":48,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"T?rkiye Bilimsel ve Teknolojik Arastirma Kurumu","doi-asserted-by":"publisher","award":["223Z129"],"award-info":[{"award-number":["223Z129"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Y-box binding protein 1 (YB-1) acts as a key oncoprotein, with its highly conserved cold shock domain (CSD) driving core nucleic acid-binding functions in cancer progression. Despite its therapeutic relevance, the CSD is considered \u201cundruggable\u201d due to the lack of a well-defined hydrophobic pocket. To overcome the limitations of rigid docking in this transient pocket, here, we present a computational ligand-prioritization workflow designed to generate experimentally testable hypotheses for this challenging target. We applied the 5D-ElectroShape formalism combined with our in-house MolPrism clustering toolkit to compress a library of \u223c11,000 RNA-protein interaction\u2013focused small molecules into 70 representative diversity centroids. These candidates were subjected to ab initio complex prediction using the deep learning-based protein folding algorithm Boltz-1, which successfully modeled the induced-fit requirements of the CSD cryptic pocket. A structure-driven selection strategy, utilizing AlphaFold-derived confidence metrics (ipTM \u2265 0.88), prioritized 18 high-confidence candidate complexes for further analysis. Subsequent molecular dynamics (MD) simulations and MM\/GBSA binding free-energy calculations were used to prioritize compounds that maintained stable pocket engagement under dynamic conditions. Among the prioritized compounds, F3382\u20130454 showed stable cryptic-pocket occupancy during MD simulations and ligand-efficiency values comparable to known YB-1 inhibitor SU056, supporting its selection as a top-ranked candidate scaffold for future testing. Taken together, these results support the use of chemical-space compression followed by generative cofolding and MD-based refinement as a practical workflow for generating hypotheses about cryptic YB-1 ligands, while experimental validation and prospective benchmarking remain necessary.<\/jats:p>","DOI":"10.1021\/acsomega.6c02840","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T22:01:35Z","timestamp":1786744895000},"page":"49432-49446","source":"Crossref","is-referenced-by-count":0,"title":["Prioritizing Candidate\nYB-1 Cold Shock Domain\nLigands via 5D-ElectroShape and Boltz Generative Cofolding"],"prefix":"10.1021","volume":"11","author":[{"given":"Lalehan","family":"Oktay","sequence":"first","affiliation":[{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34734"]},{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34734"]},{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34734"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cem","family":"Ug\u0306uz","sequence":"additional","affiliation":[{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34734"]},{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34734"]},{"name":"Biruni University , , ,","place":["Istanbul, Tu\u0308rkiye, 34015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0426-0905","authenticated-orcid":true,"given":"Serdar","family":"Durdag\u0306\u0131","sequence":"additional","affiliation":[{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34734"]},{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34734"]},{"name":"Biruni University , , ,","place":["Istanbul, Tu\u0308rkiye, 34015"]},{"name":"Bahc\u0327es\u0327ehir University , , ,","place":["Istanbul, Tu\u0308rkiye, 34353"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"issue":"11","key":"2026083119131049300_cit1","doi-asserted-by":"publisher","first-page":"4212","DOI":"10.1007\/s12033-024-01311-6","article-title":"Integrative\nInvestigation of Flavonoids Targeting YBX1 Protein\u2013Protein\nInteraction Network in Breast Cancer: From Computational Analysis\nto Experimental Validation","volume":"67","author":"Sreelekshmi","year":"2025","journal-title":"Mol. Biotechnol."},{"key":"2026083119131049300_cit2","doi-asserted-by":"publisher","first-page":"110073","DOI":"10.1016\/j.cellsig.2021.110073","article-title":"A Comprehensive\nReview of the Functions of YB-1 in Cancer Stemness, Metastasis and\nDrug Resistance","volume":"85","author":"Alkrekshi","year":"2021","journal-title":"Cell. Signal."},{"issue":"5","key":"2026083119131049300_cit3","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1111\/cas.14006","article-title":"Oncogenic Y-box Binding\nProtein-1 as an Effective Therapeutic Target in Drug-resistant Cancer","volume":"110","author":"Kuwano","year":"2019","journal-title":"Cancer Sci."},{"key":"2026083119131049300_cit4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2023\/4667089","article-title":"YB-1 Expression Is\nAssociated with Lymph Node Metastasis and Drug\nResistance to Adriamycin in Breast Cancer","volume":"2023","author":"Dong","year":"2023","journal-title":"Dis.\nMarkers"},{"issue":"3","key":"2026083119131049300_cit5","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1002\/ijc.1610","article-title":"Y-box Factor YB-1 Predicts\nDrug Resistance and Patient Outcome in Breast Cancer Independent of\nClinically Relevant Tumor Biologic Factors HER2, uPA and PAI-1","volume":"97","author":"Janz","year":"2002","journal-title":"Int. J. Cancer"},{"issue":"8","key":"2026083119131049300_cit6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI146536","article-title":"Upregulated YB-1 Protein\nPromotes Glioblastoma Growth through a YB-1\/CCT4\/mLST8\/mTOR Pathway","volume":"132","author":"Wang","year":"2022","journal-title":"J Clinical Invest."},{"issue":"33","key":"2026083119131049300_cit7","doi-asserted-by":"publisher","first-page":"55613","DOI":"10.18632\/oncotarget.14732","article-title":"Positive\nExpression of Y-Box Binding\nProtein 1 and Prognosis in Non-Small Cell Lung Cancer: A Meta-Analysis","volume":"8","author":"Jiang","year":"2017","journal-title":"Oncotarget"},{"issue":"13","key":"2026083119131049300_cit8","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1134\/S0006297911130049","article-title":"Y-Box-Binding Protein 1 (YB-1) and\nIts Functions","volume":"76","author":"Eliseeva","year":"2011","journal-title":"Biochemistry"},{"issue":"28","key":"2026083119131049300_cit9","doi-asserted-by":"publisher","first-page":"10998","DOI":"10.1074\/jbc.RA119.007545","article-title":"Crystal Structure of a Y-Box Binding\nProtein 1 (YB-1)\u2013RNA Complex Reveals Key Features and Residues\nInteracting with RNA","volume":"294","author":"Yang","year":"2019","journal-title":"J. Biol. Chem."},{"issue":"16","key":"2026083119131049300_cit10","doi-asserted-by":"publisher","first-page":"9361","DOI":"10.1093\/nar\/gkaa619","article-title":"Structural\nBasis of DNA Binding to Human YB-1 Cold Shock Domain Regulated by\nPhosphorylation","volume":"48","author":"Zhang","year":"2020","journal-title":"Nucleic Acids Res."},{"issue":"9","key":"2026083119131049300_cit11","doi-asserted-by":"publisher","first-page":"2462","DOI":"10.18632\/oncotarget.1790","article-title":"YB-1 Expression Promotes Epithelial-to-Mesenchymal\nTransition in Prostate Cancer That Is Inhibited by a Small Molecule\nFisetin","volume":"5","author":"Khan","year":"2014","journal-title":"Oncotarget"},{"issue":"4","key":"2026083119131049300_cit12","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1021\/acschembio.9b01023","article-title":"Fo\u0308rster Resonance Energy Transfer\nBased Biosensor\nfor Targeting the hNTH1\u2013YB1 Interface as a Potential Anticancer\nDrug Target","volume":"15","author":"Senarisoy","year":"2020","journal-title":"ACS Chem. Biol."},{"issue":"8","key":"2026083119131049300_cit13","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1016\/j.chembiol.2021.02.014","article-title":"Y Box\nBinding Protein 1 Inhibition as a Targeted Therapy\nfor Ovarian Cancer","volume":"28","author":"Tailor","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"2026083119131049300_cit14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.80387","article-title":"Targeting\nRNA: Protein Interactions with an Integrative Approach Leads to the\nIdentification of Potent YBX1 Inhibitors","volume":"12","author":"El Hage","year":"2023","journal-title":"Elife"},{"issue":"9","key":"2026083119131049300_cit15","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1007\/s10822-010-9374-0","article-title":"ElectroShape:\nFast Molecular Similarity\nCalculations Incorporating Shape, Chirality and Electrostatics","volume":"24","author":"Armstrong","year":"2010","journal-title":"J. Comput. Aided Mol. Des."},{"issue":"8","key":"2026083119131049300_cit16","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1007\/s10822-011-9463-8","article-title":"Improving the Accuracy\nof Ultrafast Ligand-Based Screening: Incorporating Lipophilicity into\nElectroShape as an Extra Dimension","volume":"25","author":"Armstrong","year":"2011","journal-title":"J. Comput.\nAided Mol. Des."},{"issue":"7","key":"2026083119131049300_cit17","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide:\nA New Approach for Rapid, Accurate Docking and Scoring. 1. Method\nand Assessment of Docking Accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med.\nChem."},{"issue":"7","key":"2026083119131049300_cit18","doi-asserted-by":"publisher","first-page":"3603","DOI":"10.1073\/pnas.1910862117","article-title":"Drosophila YBX1 Homolog\nYPS Promotes Ovarian Germ Line Stem Cell Development by Preferentially\nRecognizing 5-Methylcytosine RNAs","volume":"117","author":"Zou","year":"2020","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"4","key":"2026083119131049300_cit19","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1080\/15476286.2019.1710050","article-title":"YB-3 Substitutes YB-1 in Global mRNA\nBinding","volume":"17","author":"Lyabin","year":"2020","journal-title":"RNA Biol."},{"issue":"1","key":"2026083119131049300_cit20","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1093\/neuonc\/noaf227","article-title":"YBX1&YBX3 as Novel\nTargets to\nPotentiate Immune Checkpoint Blockade Response in Gliomas","volume":"28","author":"Ali","year":"2026","journal-title":"Neuro-Oncol."},{"issue":"12","key":"2026083119131049300_cit21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005690","article-title":"Compound Heterozygosity for Y Box Proteins Causes Sterility\nDue to Loss of Translational Repression","volume":"11","author":"Snyder","year":"2015","journal-title":"PLoS\nGenet."},{"issue":"11","key":"2026083119131049300_cit22","doi-asserted-by":"publisher","first-page":"2664","DOI":"10.1016\/j.celrep.2017.02.044","article-title":"LIN28 Zinc\nKnuckle Domain Is Required\nand Sufficient to Induce Let-7 Oligouridylation","volume":"18","author":"Wang","year":"2017","journal-title":"Cell Rep."},{"key":"2026083119131049300_cit23","doi-asserted-by":"publisher","first-page":"118474","DOI":"10.1016\/j.ejmech.2025.118474","article-title":"Target Validation and\nDrug Discovery for TNBC: Targeting the Lin28B\/Let-7\/PBK with the Ponicidin","volume":"304","author":"Wang","year":"2026","journal-title":"Eur. J. Med. Chem."},{"issue":"6","key":"2026083119131049300_cit24","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1021\/acsmedchemlett.0c00546","article-title":"Trisubstituted Pyrrolinones as Small-Molecule\nInhibitors Disrupting the Protein\u2013RNA Interaction of LIN28\nand Let-7","volume":"12","author":"Borgelt","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"issue":"10","key":"2026083119131049300_cit25","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.1016\/j.celrep.2018.04.116","article-title":"Small-Molecule Inhibitors\nDisrupt Let-7 Oligouridylation and Release the Selective Blockade\nof Let-7 Processing by LIN28","volume":"23","author":"Wang","year":"2018","journal-title":"Cell Rep."},{"issue":"1","key":"2026083119131049300_cit26","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.molcel.2020.03.011","article-title":"How RNA-Binding Proteins Interact\nwith RNA: Molecules and Mechanisms","volume":"78","author":"Corley","year":"2020","journal-title":"Mol. Cell"},{"issue":"9","key":"2026083119131049300_cit27","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1039\/D3SC04185A","article-title":"PoseBusters: AI-Based Docking Methods\nFail to Generate Physically Valid Poses or Generalise to Novel Sequences","volume":"15","author":"Buttenschoen","year":"2024","journal-title":"Chem. Sci."},{"issue":"5","key":"2026083119131049300_cit28","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1101\/2025.02.03.636309","article-title":"Evaluating\ngeneralization in protein-ligand\ncofolding methods","volume":"33","author":"S\u030ckrinjar","year":"2026","journal-title":"Nat. Struct. Mol. Biol."},{"issue":"1","key":"2026083119131049300_cit29","doi-asserted-by":"publisher","first-page":"8854","DOI":"10.1038\/s41467-025-63947-5","article-title":"Investigating\nWhether Deep Learning\nModels for Co-Folding Learn the Physics of Protein-Ligand Interactions","volume":"16","author":"Masters","year":"2025","journal-title":"Nat. Commun."},{"issue":"1","key":"2026083119131049300_cit30","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1021\/ci100275a","article-title":"Assessing the Performance\nof the MM\/PBSA and MM\/GBSA Methods. 1. The Accuracy of Binding Free\nEnergy Calculations Based on Molecular Dynamics Simulations","volume":"51","author":"Hou","year":"2011","journal-title":"J. Chem. Inf. Model."},{"issue":"16","key":"2026083119131049300_cit31","doi-asserted-by":"publisher","first-page":"9478","DOI":"10.1021\/acs.chemrev.9b00055","article-title":"End-Point\nBinding Free Energy Calculation with MM\/PBSA\nand MM\/GBSA: Strategies and Applications in Drug Design","volume":"119","author":"Wang","year":"2019","journal-title":"Chem. Rev."},{"issue":"3","key":"2026083119131049300_cit32","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1021\/acs.jctc.7b01295","article-title":"Computational\nAlanine Scanning with Interaction Entropy for Protein\u2013Ligand\nBinding Free Energies","volume":"14","author":"Liu","year":"2018","journal-title":"J. Chem. Theory Comput."},{"issue":"5","key":"2026083119131049300_cit33","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1016\/j.apsb.2018.12.011","article-title":"Orthogonal Assays for the Identification\nof Inhibitors of the Single-Stranded Nucleic Acid Binding Protein\nYB-1","volume":"9","author":"Trevarton","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"issue":"3","key":"2026083119131049300_cit34","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3390\/biomedicines14030545","article-title":"Computational Repurposing\nand Experimental Validation of YBX1 Inhibitors in Hepatocellular Carcinoma","volume":"14","author":"Karkoutly","year":"2026","journal-title":"Biomedicines"},{"issue":"2","key":"2026083119131049300_cit35","doi-asserted-by":"publisher","first-page":"91","DOI":"10.55730\/1300-0152.2686","article-title":"A Novel Algorithm for\nthe Virtual\nScreening of Extensive Small Molecule Libraries Against ERCC1\/XPF\nProtein-Protein Interaction for the Identification of Therapeutic\nResistance-Bypassing Small Anticancer Molecules","volume":"48","author":"Ghazy","year":"2024","journal-title":"Turkish J. Biol."},{"key":"2026083119131049300_cit36","doi-asserted-by":"publisher","DOI":"10.1101\/2024.11.19.624167","article-title":"Boltz-1 Democratizing Biomolecular Interaction Modeling","author":"Wohlwend","year":"2025","journal-title":"bioRxiv"},{"key":"2026083119131049300_cit37","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1109\/SC.2006.54","article-title":"Scalable Algorithms\nfor Molecular Dynamics Simulations on Commodity Clusters","volume-title":"SC\u201906: Proceedings of the 2006 ACM\/IEEE Conference\non Supercomputing","author":"Bowers","year":"2006"},{"issue":"2","key":"2026083119131049300_cit38","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison\nof Simple Potential Functions for Simulating Liquid Water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"issue":"3","key":"2026083119131049300_cit39","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1021\/acs.jctc.8b01026","article-title":"OPLS3e: Extending\nForce Field Coverage for Drug-Like Small Molecules","volume":"15","author":"Roos","year":"2019","journal-title":"J. Chem. Theory Comput."},{"issue":"4","key":"2026083119131049300_cit40","doi-asserted-by":"publisher","first-page":"2635","DOI":"10.1063\/1.463940","article-title":"Nose\u0301\u2013Hoover\nChains:\nThe Canonical Ensemble via Continuous Dynamics","volume":"97","author":"Martyna","year":"1992","journal-title":"J. Chem. Phys."},{"issue":"5","key":"2026083119131049300_cit41","doi-asserted-by":"publisher","first-page":"4177","DOI":"10.1063\/1.467468","article-title":"Constant\nPressure Molecular Dynamics\nAlgorithms","volume":"101","author":"Martyna","year":"1994","journal-title":"J. Chem. Phys."},{"issue":"3","key":"2026083119131049300_cit42","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1063\/1.463137","article-title":"Reversible\nMultiple Time Scale Molecular\nDynamics","volume":"97","author":"Tuckerman","year":"1992","journal-title":"J. Chem. Phys."},{"issue":"12","key":"2026083119131049300_cit43","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle Mesh\nEwald: An N\u00b7log(N)\nMethod for Ewald Sums in Large Systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem.\nPhys."},{"issue":"5814","key":"2026083119131049300_cit44","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1126\/science.1136800","article-title":"Clustering by passing Messages Between Data Points","volume":"315","author":"Frey","year":"2007","journal-title":"Science"},{"issue":"10","key":"2026083119131049300_cit45","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1002\/prot.23106","article-title":"The VSGB 2.0 Model: A next Generation\nEnergy Model\nfor High Resolution Protein Structure Modeling","volume":"79","author":"Li","year":"2011","journal-title":"Proteins: struct., Funct., Bioinf."},{"issue":"14","key":"2026083119131049300_cit46","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1093\/nar\/gkf436","article-title":"MAFFT: A Novel\nMethod for Rapid Multiple Sequence Alignment Based on Fast Fourier\nTransform","volume":"30","author":"Katoh","year":"2002","journal-title":"Nucleic Acids Res."},{"issue":"4","key":"2026083119131049300_cit47","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1093\/bib\/bbx108","article-title":"MAFFT Online Service: Multiple Sequence\nAlignment, Interactive Sequence Choice and Visualization","volume":"20","author":"Katoh","year":"2019","journal-title":"Briefings Bioinf."},{"issue":"W1","key":"2026083119131049300_cit48","doi-asserted-by":"publisher","first-page":"W320","DOI":"10.1093\/nar\/gku316","article-title":"Deciphering Key Features\nin Protein Structures with the New ENDscript\nServer","volume":"42","author":"Robert","year":"2014","journal-title":"Nucleic Acids Res."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c02840","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49432\/66577325\/acsomega.6c02840.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49432\/66577325\/acsomega.6c02840.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:13:18Z","timestamp":1788217998000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/33\/49432\/5257488\/Prioritizing-Candidate-YB-1-Cold-Shock-Domain"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":48,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,14]]},"published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c02840","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}