{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T07:56:48Z","timestamp":1772783808763,"version":"3.50.1"},"reference-count":143,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T00:00:00Z","timestamp":1729814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Partnership on Metrology","award":["5056"],"award-info":[{"award-number":["5056"]}]},{"name":"European Union\u2019s Horizon Europe Research and Innovation Programme","award":["5056"],"award-info":[{"award-number":["5056"]}]},{"name":"Participating States","award":["5056"],"award-info":[{"award-number":["5056"]}]},{"name":"EMBO Installation","award":["5056"],"award-info":[{"award-number":["5056"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission. Methods: Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously. Results: A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3\u20138 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties. Conclusions: Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target\u2013drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML.<\/jats:p>","DOI":"10.3390\/cancers16213607","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T10:50:08Z","timestamp":1729853408000},"page":"3607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Computer-Aided Identification and Design of Ligands for Multi-Targeting Inhibition of a Molecular Acute Myeloid Leukemia Network"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9134-7517","authenticated-orcid":false,"given":"Seyedeh Sadaf","family":"Asfa","sequence":"first","affiliation":[{"name":"Izmir Biomedicine and Genome Center, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada"},{"name":"Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R3E 0W2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5710-7481","authenticated-orcid":false,"given":"Reza","family":"Arshinchi Bonab","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada"},{"name":"Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R3E 0W2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8373-1233","authenticated-orcid":false,"given":"Onur","family":"\u00d6nder","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3237-8959","authenticated-orcid":false,"given":"Merve","family":"U\u00e7a Apayd\u0131n","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5940-279X","authenticated-orcid":false,"given":"Hatice","family":"D\u00f6\u015feme","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5540-9012","authenticated-orcid":false,"given":"Can","family":"K\u00fc\u00e7\u00fck","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Dokuz Eyl\u00fcl University, 35330 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5971-0010","authenticated-orcid":false,"given":"Alexandros G.","family":"Georgakilas","sequence":"additional","affiliation":[{"name":"Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou Campous, 15780 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6171-6921","authenticated-orcid":false,"given":"Bernhard M.","family":"Stadler","sequence":"additional","affiliation":[{"name":"Technische Hochschule N\u00fcrnberg, Faculty of Applied Chemistry, 90489 Nuremberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella","family":"Logotheti","sequence":"additional","affiliation":[{"name":"Biomedical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7903-8543","authenticated-orcid":false,"given":"Seyit","family":"Kale","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Department of Biophysics, Faculty of Medicine, Izmir Katip \u00c7elebi University, 35330 \u00c7i\u011fli, \u0130zmir, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-3808","authenticated-orcid":false,"given":"Athanasia","family":"Pavlopoulou","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, 35340 Bal\u00e7ova, \u0130zmir, T\u00fcrkiye"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, 35340 Bal\u00e7ova, \u0130zmir, 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