{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:16:31Z","timestamp":1783070191987,"version":"3.54.6"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>AKT1 and AKT2 are central but functionally distinct kinases within the PI3K\u2013AKT\u2013mTOR pathway, and isoform\u2010specific genomic alterations in these proteins have important implications for cancer prognosis and therapeutic responsiveness. This study aimed to integrate cancer pharmacogenomics with structure\u2010based modeling to identify natural compounds capable of selectively targeting AKT1 or AKT2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Public cancer genomics datasets from TCGA and the Kaplan\u2013Meier Plotter were analyzed to characterize mutation patterns, copy number alterations, and survival associations of AKT1 and AKT2 across malignancies. Based on isoform-specific differences, twenty phytochemicals from Pithecellobium dulce were docked against the allosteric binding sites of AKT1 (PDB: 3QKL) and AKT2 (PDB: 2JDO). Lead compounds were evaluated using ADME prediction and density functional theory to assess pharmacokinetic suitability and electronic stability. The dynamic behavior of ligand\u2013protein complexes was examined through 200\u2010ns molecular dynamics simulations using the Desmond\u2013Schr\u00f6dinger platform, and binding free energies were estimated via MM\u2010GBSA analysis. Regulatory interactions involving AKT\u2010associated non\u2010coding RNAs were also examined to support pharmacogenomic relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Genomic analysis revealed that AKT1 alterations were dominated by activating missense mutations, particularly the E17K hotspot, whereas AKT2 showed frequent gene amplifications that were significantly associated with poor overall survival. Docking studies demonstrated clear isoform selectivity among P. dulce phytochemicals: oleanolic acid and pitheduloside I preferentially bound AKT1, while rutin and naringin exhibited stronger affinity toward AKT2. Oleanolic acid and rutin displayed binding energies comparable to established allosteric AKT inhibitors. ADME and DFT analyses supported favorable drug\u2010likeness and molecular stability of the lead compounds. Molecular dynamics simulations confirmed stable complex formation with persistent hydrogen bonding, and MM\u2010GBSA calculations indicated superior binding energetics for oleanolic acid\u2013AKT1 and rutin\u2013AKT2 complexes relative to controls. In parallel, analysis of miR-149\u20105p and lncRNA HOTAIR highlighted post\u2010transcriptional regulatory mechanisms influencing AKT isoform activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates that integrating pharmacogenomic profiling with multiscale molecular simulations can reveal isoform\u2010specific vulnerabilities within the AKT signaling axis. Phytochemicals derived from Pithecellobium dulce, particularly oleanolic acid and rutin, emerge as promising selective modulators of AKT1 and AKT2, respectively. These findings provide a mechanistic and structural foundation for the development of isoform\u2010guided AKT\u2010targeted therapies and support further experimental validation toward precision oncology applications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1744408","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T06:30:35Z","timestamp":1770100235000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacogenomic and in silico identification of isoform-selective AKT inhibitors from Pithecellobium dulce for precision cancer therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Gnanaprakash","family":"Jeyaraj","sequence":"first","affiliation":[{"name":"Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences","place":["Chennai, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Public Health, International School, Krirk University","place":["Bangkok, Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuppusamy","family":"Sathishkumar","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Rathinam College of Arts and Science","place":["Coimbatore, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh","family":"Chokkakula","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute","place":["Cheongju, Chungbuk, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bader O.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University","place":["Riyadh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Affiliated Hengyang Hospital of Hunan Normal University & Hengyang Central Hospital","place":["Hengyang, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"117334","DOI":"10.1016\/j.ejmech.2025.117334","article-title":"Structural requirements of isoform-specific inhibitors of Akt: implications in the development of effective cancer treatment strategies","volume":"287","author":"Adon","year":"2025","journal-title":"Eur. 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