{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:03:01Z","timestamp":1787022181663,"version":"build-2736575974"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background\/objectives<\/jats:title>\n                    <jats:p>\n                      Colorectal cancer is characterized by various oncogenic mutations, with the KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      mutation being the most prevalent. The development of MRTX1133 has revitalized the KRAS direct targeting. However, colorectal cancer demonstrated intrinsic resistance to MRTX1133, primarily due to the feedback activation of the EGFR pathway. Combining KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      and EGFR inhibition has demonstrated improved treatment efficacy, highlighting the potential of dual-targeting approaches in colorectal cancer therapy. This study employs CADD tools to identify approved drugs capable of dual targeting KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      and EGFR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A library of 3,591 approved drugs was screened against KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      using high-throughput virtual screening (HTVs), standard precision (SP) and extra precision (XP) Glide docking modules. The top-ranking compounds were then docked into the EGFR binding pocket using XP mode, and docking scores were calculated. Further refinement of binding affinities was performed using Molecular Mechanics with Generalized Born and Surface Area Solvation (MM-GBSA) and Molecular Dynamics (MD) simulations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 25 drugs showed better affinity to KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      than MRTX1133 (\u22129.18 kcal\/mol). Among them, six drugs: Reproterol, Macimorelin, Nebivolol, Nadolol, Antrafenine, and Carteolol, displayed docking scores between \u22127.186 and \u22128.864 kcal\/mol against EGFR, compared to the reference ligand Erlotinib (\u22129.669 kcal\/mol). Subsequent MM-GBSA and MD identified Carteolol, an FDA-approved beta blocker, as the most promising candidate, showing stable and reliable binding with KRAS\n                      <jats:sup>G12D<\/jats:sup>\n                      and relatively stable interactions with EGFR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This\n                      <jats:italic>in silico<\/jats:italic>\n                      study predicts Carteolol as a potential dual-targeting therapeutic agent, requiring biochemical and cellular validation before clinical relevance can be established.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0338123","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T18:27:37Z","timestamp":1769624857000},"page":"e0338123","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational repurposing of approved drugs targeting KRAS G12D and EGFR for colorectal cancer therapy"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4484-9367","authenticated-orcid":true,"given":"Walaa","family":"Ibraheem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Alsheikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrahim A.","family":"Alzain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhoomendra A.","family":"Bhongade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila","family":"Ejaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamnah","family":"Baig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"El-Tanani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"pone.0338123.ref001","first-page":"405","article-title":"Sensitivity","volume":"22","author":"EK Ziemke","year":"2017","journal-title":"Cancer Research"},{"key":"pone.0338123.ref002","doi-asserted-by":"crossref","first-page":"1013902","DOI":"10.3389\/fonc.2022.1013902","article-title":"KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?","volume":"12","author":"SF Bannoura","year":"2022","journal-title":"Front Oncol"},{"issue":"1","key":"pone.0338123.ref003","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41392-021-00780-4","article-title":"KRAS mutation: from undruggable to druggable in cancer","volume":"6","author":"L Huang","year":"2021","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"pone.0338123.ref004","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/s13045-022-01375-4","article-title":"Drugging KRAS: current perspectives and state-of-art review","volume":"15","author":"K Parikh","year":"2022","journal-title":"J Hematol Oncol"},{"issue":"18","key":"pone.0338123.ref005","doi-asserted-by":"crossref","first-page":"3394","DOI":"10.7150\/jca.26068","article-title":"Antitumor activity of sorafenib plus CDK4\/6 inhibitor in pancreatic patient derived cell with KRAS mutation","volume":"9","author":"T Lee","year":"2018","journal-title":"J Cancer"},{"issue":"4","key":"pone.0338123.ref006","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1158\/2159-8290.CD-21-1331","article-title":"Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants","volume":"12","author":"MH Hofmann","year":"2022","journal-title":"Cancer Discov"},{"issue":"4","key":"pone.0338123.ref007","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1158\/1078-0432.CCR-23-2098","article-title":"A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer","volume":"30","author":"D Wei","year":"2024","journal-title":"Clin Cancer Res"},{"key":"pone.0338123.ref008","unstructured":"Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, et al. 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