{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:13:51Z","timestamp":1789395231886,"version":"build-2803163510"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"17","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100015378","name":"Shanghai University of Medicine and Health Sciences","doi-asserted-by":"publisher","award":["HXXM-25-01-002"],"award-info":[{"award-number":["HXXM-25-01-002"]}],"id":[{"id":"10.13039\/501100015378","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019033","name":"Key Research and Development Program of Liaoning Province","doi-asserted-by":"publisher","award":["2021JH1\/10400050"],"award-info":[{"award-number":["2021JH1\/10400050"]}],"id":[{"id":"10.13039\/501100019033","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Multidrug resistance (MDR) mediated by ATP-binding cassette transporter G2 (ABCG2) remains a major clinical challenge in breast cancer chemotherapy, primarily due to its role in reducing intracellular adriamycin (ADR) concentrations. To address this challenge, we developed an integrated computational strategy for the rapid identification of potent ABCG2 inhibitors capable of reversing ADR resistance. We first established the Prediction of Protein\u2013Ligand\u2019s pKd (PPLK), a specialized deep learning model that employs multimodal sequence-ligand representations and feedforward neural networks to accelerate the discovery of ABCG2 inhibitors. Next, computational virtual screening of a compound library (\u223c1.58 million) was conducted, coupled with molecular dynamics simulations, focusing on the key binding residues THR542, PHE439, ASN436, and SER440. Among the top-ranked candidates, reserpine was validated as a potent ABCG2 inhibitor, achieving 1.90-fold sensitization in ADR-resistant cells, thereby confirming the predictive accuracy of the PPLK model. Notably, we identified a small-molecule compound, F0161-0219, as a promising ABCG2 inhibitor, which led to a 1.94-fold sensitization enhancement in ADR-resistant cells. Direct target engagement of F0161-0219 with ABCG2 was confirmed by biolayer interferometry, DARTS, and CETSA assays. Collectively, our research underscores the potential of leveraging deep learning models and computational screening for the discovery of ABCG2 inhibitors.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c00582","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:13:34Z","timestamp":1788412414000},"page":"11174-11190","source":"Crossref","is-referenced-by-count":0,"title":["Leveraging a Deep\nLearning Model and Computational\nScreening for the Discovery of ABCG2 Inhibitors against Drug-Resistant\nBreast Cancer"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6638-1518","authenticated-orcid":true,"given":"Haonan","family":"Li","sequence":"first","affiliation":[{"name":"Dalian University of Technology , , , ,","place":["Dalian, Liaoning, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zichu","family":"Wang","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , , ,","place":["Dalian, Liaoning, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[{"name":"Dalian Medical University , , , ,","place":["Dalian, Liaoning, China, 116044"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0449-0599","authenticated-orcid":true,"given":"Yongliang","family":"Yang","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , , ,","place":["Dalian, Liaoning, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"issue":"11","key":"2026091409064837700_cit1","doi-asserted-by":"publisher","first-page":"2666","DOI":"10.3390\/cancers13112666","article-title":"Emerging Insights into Targeted Therapy-Tolerant Persister\nCells in Cancer","volume":"13","author":"Cabanos","year":"2021","journal-title":"Cancers"},{"issue":"10","key":"2026091409064837700_cit2","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12894","article-title":"Cellular senescence\nand cancer: Focusing on traditional Chinese medicine and natural products","volume":"53","author":"Liu","year":"2020","journal-title":"Cell Proliferation"},{"issue":"25","key":"2026091409064837700_cit3","doi-asserted-by":"publisher","first-page":"3267","DOI":"10.2174\/092986709788803312","article-title":"Doxorubicin: the good, the bad and\nthe ugly effect","volume":"16","author":"Carvalho","year":"2009","journal-title":"Curr. Med. Chem."},{"issue":"7","key":"2026091409064837700_cit4","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/s41568-018-0005-8","article-title":"Revisiting the role of ABC transporters in multidrug-resistant\ncancer","volume":"18","author":"Robey","year":"2018","journal-title":"Nat. Rev. Cancer"},{"issue":"1","key":"2026091409064837700_cit5","doi-asserted-by":"publisher","first-page":"105","DOI":"10.2217\/14622416.9.1.105","article-title":"ABC multidrug\ntransporters: structure, function and role in chemoresistance","volume":"9","author":"Sharom","year":"2008","journal-title":"Pharmacogenomics"},{"issue":"7731","key":"2026091409064837700_cit6","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41586-018-0680-3","article-title":"Cryo-EM structures\nof a human ABCG2 mutant trapped\nin ATP-bound and substrate-bound states","volume":"563","author":"Manolaridis","year":"2018","journal-title":"Nature"},{"issue":"7659","key":"2026091409064837700_cit7","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/nature22345","article-title":"Structure of the human multidrug transporter ABCG2","volume":"546","author":"Taylor","year":"2017","journal-title":"Nature"},{"issue":"13","key":"2026091409064837700_cit8","doi-asserted-by":"publisher","first-page":"166980","DOI":"10.1016\/j.jmb.2021.166980","article-title":"Structural Basis\nof Drug Recognition by the Multidrug\nTransporter ABCG2","volume":"433","author":"Kowal","year":"2021","journal-title":"J. Mol. Biol."},{"issue":"1","key":"2026091409064837700_cit9","doi-asserted-by":"publisher","first-page":"4376","DOI":"10.1038\/s41467-021-24651-2","article-title":"Structures of ABCG2 under turnover conditions reveal\na key step in the drug transport mechanism","volume":"12","author":"Yu","year":"2021","journal-title":"Nat. Commun."},{"issue":"1","key":"2026091409064837700_cit10","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1038\/s41467-020-16155-2","article-title":"ABCG2 transports anticancer\ndrugs via a closed-to-open switch","volume":"11","author":"Orlando","year":"2020","journal-title":"Nat. Commun."},{"issue":"4","key":"2026091409064837700_cit11","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41594-018-0049-1","article-title":"Structural basis of\nsmall-molecule inhibition of human multidrug transporter ABCG2","volume":"25","author":"Jackson","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"issue":"9","key":"2026091409064837700_cit12","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1007\/s12272-015-0640-5","article-title":"Role of computer-aided\ndrug design in modern drug discovery","volume":"38","author":"Macalino","year":"2015","journal-title":"Arch.\nPharmacal Res."},{"issue":"3","key":"2026091409064837700_cit13","doi-asserted-by":"crossref","DOI":"10.3390\/ijms24032026","article-title":"Artificial\nIntelligence and Machine\nLearning Technology Driven Modern Drug Discovery and Development","volume":"24","author":"Sarkar","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"2026091409064837700_cit14","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.sbi.2021.10.001","article-title":"Deep learning approaches for de novo\ndrug design: An overview","volume":"72","author":"Wang","year":"2022","journal-title":"Curr. Opin. Struct.\nBiol."},{"issue":"4","key":"2026091409064837700_cit15","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.cell.2020.01.021","article-title":"A Deep Learning Approach to Antibiotic\nDiscovery","volume":"180","author":"Stokes","year":"2020","journal-title":"Cell"},{"key":"2026091409064837700_cit16","article-title":"Modeling protein-ligand interactions\nfor drug discovery\nin the era of deep learning","author":"Wang","year":"2025","journal-title":"Chem. Soc. Rev."},{"issue":"Pt A","key":"2026091409064837700_cit17","doi-asserted-by":"publisher","first-page":"110438","DOI":"10.1016\/j.compbiomed.2025.110438","article-title":"Drug-target\ninteraction\/affinity\nprediction: Deep learning models and advances review","volume":"196","author":"Vefghi","year":"2025","journal-title":"Comput. Biol. Med."},{"issue":"1","key":"2026091409064837700_cit18","doi-asserted-by":"publisher","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\nAcids Res."},{"issue":"2","key":"2026091409064837700_cit19","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.phymed.2015.01.002","article-title":"Cytotoxicity of the indole alkaloid reserpine from\nRauwolfia serpentina against drug-resistant tumor cells","volume":"22","author":"Abdelfatah","year":"2015","journal-title":"Phytomedicine"},{"issue":"23","key":"2026091409064837700_cit20","doi-asserted-by":"publisher","first-page":"5734","DOI":"10.1111\/bph.70215","article-title":"Pathway-level\nmutational signatures predict breast\ncancer outcomes and reveal therapeutic targets","volume":"182","author":"Posta","year":"2025","journal-title":"Br. J. Pharmacol."},{"issue":"1","key":"2026091409064837700_cit21","doi-asserted-by":"publisher","first-page":"13767","DOI":"10.1038\/s41598-017-11794-w","article-title":"The structure\nof the human ABC transporter\nABCG2 reveals a novel mechanism for drug extrusion","volume":"7","author":"Khunweeraphong","year":"2017","journal-title":"Sci. Rep."},{"issue":"19","key":"2026091409064837700_cit22","doi-asserted-by":"publisher","first-page":"168234","DOI":"10.1016\/j.jmb.2023.168234","article-title":"Structural Basis\nof the Allosteric Inhibition of Human ABCG2 by Nanobodies","volume":"435","author":"Irobalieva","year":"2023","journal-title":"J. Mol. Biol."},{"issue":"38","key":"2026091409064837700_cit23","doi-asserted-by":"publisher","first-page":"26059","DOI":"10.1074\/jbc.M803230200","article-title":"Interaction with the\n5D3 monoclonal antibody is regulated by intramolecular rearrangements\nbut not by covalent dimer formation of the human ABCG2 multidrug transporter","volume":"283","author":"Ozvegy-Laczka","year":"2008","journal-title":"J. Biol. Chem."},{"issue":"21","key":"2026091409064837700_cit24","doi-asserted-by":"publisher","first-page":"18633","DOI":"10.1021\/acs.jmedchem.4c02462","article-title":"Current Status\nof Computational Approaches for Small Molecule Drug Discovery","volume":"67","author":"Xu","year":"2024","journal-title":"J. Med. Chem."},{"issue":"7805","key":"2026091409064837700_cit25","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/s41586-020-2117-z","article-title":"An open-source drug\ndiscovery platform enables ultra-large virtual screens","volume":"580","author":"Gorgulla","year":"2020","journal-title":"Nature"},{"issue":"1","key":"2026091409064837700_cit26","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1021\/acsmedchemlett.0c00517","article-title":"Discovery\nof Aminopyrazole\nDerivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant\nFGFR2 and 3","volume":"12","author":"Brawn","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"issue":"15","key":"2026091409064837700_cit27","doi-asserted-by":"publisher","first-page":"10473","DOI":"10.1021\/acs.jmedchem.3c00600","article-title":"Discovery of a Potent and Selective Tyrosine Kinase\n2 Inhibitor: TAK-279","volume":"66","author":"Leit","year":"2023","journal-title":"J. Med. Chem."},{"key":"2026091409064837700_cit28","first-page":"31397","article-title":"Unified Generative\nModeling of 3D Molecules for De Novo Binder Design","volume-title":"Proceedings of Machine Learning Research (PMLR)","author":"Liu","year":"2025"},{"issue":"1","key":"2026091409064837700_cit29","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s43856-025-01209-7","article-title":"A multimodal framework for comprehensive driver variant prediction\nin cancer","volume":"5","author":"Yang","year":"2025","journal-title":"Commun. Med."},{"issue":"9","key":"2026091409064837700_cit30","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1021\/acs.chemrestox.5c00225","article-title":"Inhibitory Effects\nof Alkaloids on BCRP Implicated in Reversing Multidrug Resistance:\nA Case Example of Enhancing Temozolomide Cytotoxicity","volume":"38","author":"Duan","year":"2025","journal-title":"Chem. Res. Toxicol."},{"issue":"10","key":"2026091409064837700_cit31","doi-asserted-by":"publisher","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A New Tool\nto Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valdes-Tresanco","year":"2021","journal-title":"J. Chem. Theory Comput."},{"issue":"1","key":"2026091409064837700_cit32","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1002\/jcc.23108","article-title":"FIPSDock: a new molecular\ndocking technique driven by fully informed\nswarm optimization algorithm","volume":"34","author":"Liu","year":"2013","journal-title":"J. Comput. Chem."},{"issue":"9","key":"2026091409064837700_cit33","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/j.chembiol.2014.08.013","article-title":"Oral Druggable Space\nbeyond the Rule of 5: Insights from Drugs and Clinical Candidates","volume":"21","author":"Doak","year":"2014","journal-title":"Chem. Biol."},{"issue":"19","key":"2026091409064837700_cit34","doi-asserted-by":"publisher","first-page":"7422","DOI":"10.1021\/acs.jcim.4c00913","article-title":"Discovery\nof Potent Covalent CRM1 Inhibitors Via a Customized Structure-Based\nVirtual Screening Pipeline and Bioassays","volume":"64","author":"Liu","year":"2024","journal-title":"J.\nChem. Inf. Model."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c00582","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/11174\/68029252\/acs.jcim.6c00582.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/11174\/68029252\/acs.jcim.6c00582.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:15:26Z","timestamp":1789391726000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/17\/11174\/5388498\/Leveraging-a-Deep-Learning-Model-and-Computational"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":34,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,8,31]]},"published-print":{"date-parts":[[2026,9,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c00582","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}