{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T10:06:48Z","timestamp":1769940408601,"version":"3.49.0"},"reference-count":87,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T00:00:00Z","timestamp":1703635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Computation"],"abstract":"<jats:p>The prognosis of mixed-lineage leukemia (MLL) has remained a significant health concern, especially for infants. The minimal treatments available for this aggressive type of leukemia has been an ongoing problem. Chromosomal translocations of the KMT2A gene are known as MLL, which expresses MLL fusion proteins. A protein called menin is an important oncogenic cofactor for these MLL fusion proteins, thus providing a new avenue for treatments against this subset of acute leukemias. In this study, we report results using the structure-based drug design (SBDD) approach to discover potential novel MLL-mediated leukemia inhibitors from natural products against menin. The three-dimensional (3D) protein model was derived from Protein Databank (Protein ID: 4GQ4), and EasyModeller 4.0 and I-TASSER were used to fix missing residues during rebuilding. Out of the ten protein models generated (five from EasyModeller and I-TASSER each), one model was selected. The selected model demonstrated the most reasonable quality and had 75.5% of residues in the most favored regions, 18.3% of residues in additionally allowed regions, 3.3% of residues in generously allowed regions, and 2.9% of residues in disallowed regions. A ligand library containing 25,131 ligands from a Chinese database was virtually screened using AutoDock Vina, in addition to three known menin inhibitors. The top 10 compounds including ZINC000103526876, ZINC000095913861, ZINC000095912705, ZINC000085530497, ZINC000095912718, ZINC000070451048, ZINC000085530488, ZINC000095912706, ZINC000103580868, and ZINC000103584057 had binding energies of \u221211.0, \u221210.7, \u221210.6, \u221210.2, \u221210.2, \u22129.9, \u22129.9, \u22129.9, \u22129.9, and \u22129.9 kcal\/mol, respectively. To confirm the stability of the menin\u2013ligand complexes and the binding mechanisms, molecular dynamics simulations including molecular mechanics Poisson\u2013Boltzmann surface area (MM\/PBSA) computations were performed. The amino acid residues that were found to be potentially crucial in ligand binding included Phe243, Met283, Cys246, Tyr281, Ala247, Ser160, Asn287, Asp185, Ser183, Tyr328, Asn249, His186, Leu182, Ile248, and Pro250. MI-2-2 and PubChem CIDs 71777742 and 36294 were shown to possess anti-menin properties; thus, this justifies a need to experimentally determine the activity of the identified compounds. The compounds identified herein were found to have good pharmacological profiles and had negligible toxicity. Additionally, these compounds were predicted as antileukemic, antineoplastic, chemopreventive, and apoptotic agents. The 10 natural compounds can be further explored as potential novel agents for the effective treatment of MLL-mediated leukemia.<\/jats:p>","DOI":"10.3390\/computation12010003","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T05:43:15Z","timestamp":1703655795000},"page":"3","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Design of Inhibitors That Target the Menin\u2013Mixed-Lineage Leukemia Interaction"],"prefix":"10.3390","volume":"12","author":[{"given":"Moses N.","family":"Arthur","sequence":"first","affiliation":[{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra LG 581, Ghana"},{"name":"Biomedical Engineering Department, University of Rochester, Rochester, NY 14627, USA"}]},{"given":"Kristeen","family":"Bebla","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"},{"name":"Department of Molecular Pharmacology & Neuroscience, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6793-7530","authenticated-orcid":false,"given":"Emmanuel","family":"Broni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"}]},{"given":"Carolyn","family":"Ashley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"}]},{"given":"Miriam","family":"Velazquez","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"}]},{"given":"Xianin","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0686-2851","authenticated-orcid":false,"given":"Ravi","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1093-1517","authenticated-orcid":false,"given":"Samuel K.","family":"Kwofie","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra LG 77, Ghana"},{"name":"Department of Biochemistry, Cell and Molecular Biology, West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra LG 54, Ghana"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-7940","authenticated-orcid":false,"suffix":"III","given":"Whelton A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"},{"name":"Department of Molecular Pharmacology & Neuroscience, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"},{"name":"Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.ccell.2019.11.001","article-title":"A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia","volume":"36","author":"Krivtsov","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/bies.201200007","article-title":"Menin as a hub controlling mixed lineage leukemia","volume":"34","author":"Thiel","year":"2012","journal-title":"BioEssays"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15519","DOI":"10.1021\/acs.jmedchem.1c00872","article-title":"Recent Progress of Small Molecule Menin\u2013MLL Interaction Inhibitors as Therapeutic Agents for Acute Leukemia","volume":"64","author":"Lei","year":"2021","journal-title":"J. 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