{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T01:08:38Z","timestamp":1789348118777,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PID2023\u2010150717NB\u2010I00"],"award-info":[{"award-number":["PID2023\u2010150717NB\u2010I00"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004242","name":"Princess Nora University","doi-asserted-by":"publisher","award":["PNURSP2026R5"],"award-info":[{"award-number":["PNURSP2026R5"]}],"id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,9,14]]},"abstract":"<jats:p>\n                    The S\u2010phase kinase\u2010associated protein 2 (Skp2)\u2013cyclin\u2010dependent kinase subunit 1 (Cks1) protein\u2013protein interaction (PPI) plays a central role in recognition of phosphorylated p27 and therefore represents an attractive target for anticancer drug discovery. Herein, we sought to identify new small\u2010molecule disruptors of the Skp2\u2013Cks1 interface from a focused fumiquinazoline\u2010scaffold library by combining virtual screening, molecular simulation, and experimental validation. Docking showed that all selected compounds occupied the Skp2\u2013Cks1 interfacial hotspot. However, longer 1000\u2010ns MD simulations, comparative MM\/PBSA calculations, and interface\u2010related metrics revealed distinct structural, energetic, and dynamic binding profiles among the selected compounds. Consistent with these analyses, comparative MM\/PBSA evaluation of PPI stability showed that Fumiquinazoline D produced a positive , indicating weakening of the Skp2\u2013Cks1 interface relative to the apo complex, whereas Ardeemin, Fiscalin A, and Fumiquinazoline F generally yielded negative  values consistent with interfacial stabilization. Free energy landscape analysis further supported a more weakly confined and dynamically disruptive binding mode for Fumiquinazoline\u2010 D. In vitro homogeneous time\u2010resolved fluorescence assays validated these predictions: Fumiquinazoline D inhibited the Skp2\u2013Cks1 interaction with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 6.33 \u00b1 0.44\u2009\u00b5M, whereas Ardeemin, Fiscalin A, and Fumiquinazoline F were substantially weaker. Although ADMET profiling identified substantial absorption and toxicity liabilities requiring future optimization, these findings identify Fumiquinazoline D as an early\u2010stage biochemical hit for disruption of the Skp2\u2013Cks1 interaction and as a potential scaffold for further mechanistic validation and medicinal\u2010chemistry investigation.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70470","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T02:04:16Z","timestamp":1787969056000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2010Based Discovery of Fumiquinazolines as Skp2\u2013Cks1 Protein\u2013Protein Interaction Disruptors: Mechanistic Computational Insights and Experimental Validation"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1279-9564","authenticated-orcid":false,"given":"Emadeldin M.","family":"Kamel","sequence":"first","affiliation":[{"name":"Chemistry Department Faculty of Science Beni\u2010Suef University  Beni\u2010Suef Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Allam","sequence":"additional","affiliation":[{"name":"Department of Biology College of Science Imam Mohammad Ibn Saud Islamic University (IMSIU)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan A.","family":"Rudayni","sequence":"additional","affiliation":[{"name":"Department of Biology College of Science Imam Mohammad Ibn Saud Islamic University (IMSIU)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah I.","family":"Othman","sequence":"additional","affiliation":[{"name":"Department of Biology College of Science Princess Nourah bint Abdulrahman University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad M.","family":"Alshabrmi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories College of Applied Medical Sciences Qassim University  Buraydah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faris F. Aba","family":"Alkhayl","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories College of Applied Medical Sciences Qassim University  Buraydah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al Mokhtar","family":"Lamsabhi","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica and Institute for Advanced Research in Chemical Science (IAdChem) Facultad de Ciencias, M\u00f3dulo 13 Universidad Aut\u00f3noma de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/35060126"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00210-6"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405944200"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.09.003"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2020.01.013"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2025.178129"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-37609-9"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-00646-3"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11696\u2010026\u201005243\u20100"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02036-3"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/pca.70054"},{"key":"e_1_2_13_13_1","first-page":"717","volume-title":"Methods in Enzymology","author":"Huang K. 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