{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T10:25:16Z","timestamp":1787135116635,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007446","name":"King Khalid University","doi-asserted-by":"publisher","award":["RGP1\/263\/46"],"award-info":[{"award-number":["RGP1\/263\/46"]}],"id":[{"id":"10.13039\/501100007446","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RGP1\/263\/46"],"award-info":[{"award-number":["RGP1\/263\/46"]}],"id":[{"id":"https:\/\/ror.org\/052kwzs30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Mitogen-activated protein kinase 3 (MAPK3\/ERK1) plays a central role in cellular proliferation, inflammation, apoptosis, and survival signalling and has been implicated in oral squamous cell carcinoma (OSCC), periodontitis, oral lichen planus, and other chronic oral inflammatory diseases. The present study employed an integrated computational workflow combining machine learning (ML)-based quantitative structure\u2013activity relationship (QSAR) modelling, molecular docking, density functional theory (DFT), molecular dynamics (MD) simulation, and MM-GBSA analysis to identify and characterise potent MAPK3 inhibitors. Methods: A curated dataset of 907 experimentally validated MAPK3 inhibitors was retrieved from the ChEMBL database and processed using molecular descriptors and Morgan fingerprints. Multiple ML algorithms were evaluated under scaffold-based validation, with Light Gradient Boosting Machine (LightGBM) demonstrating the best predictive performance. Results: The final model achieved strong classification capability with ROC-AUC values of 0.898 and 0.926. Feature importance analysis revealed that local structural motifs captured by fingerprint descriptors played dominant roles in MAPK3 inhibitory activity. The top-ranked compounds were subjected to molecular docking, where compounds 58324148 and 137531515 exhibited strong binding affinities of \u221211.9 and \u221211.0 kcal\/mol, respectively. DFT calculations demonstrated favourable electronic properties with low HOMO\u2013LUMO energy gaps, while MD simulations confirmed stable receptor\u2013ligand interactions throughout 200 ns trajectories. MM-GBSA analysis further supported strong binding stability dominated by van der Waals interactions. Conclusions: Overall, the integrated computational framework successfully identified promising MAPK3 inhibitor candidates with potential therapeutic relevance for oral inflammatory and proliferative diseases.<\/jats:p>","DOI":"10.3390\/ph19081309","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:30:53Z","timestamp":1787131853000},"page":"1309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated AI-Driven Discovery of MAPK3 Inhibitors for Oral Inflammatory and Proliferative Diseases"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5868-3527","authenticated-orcid":false,"given":"Muhammad","family":"Ishfaq","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahi Jahan","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imran","family":"Khalid","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mashail M. M.","family":"Hamid","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Zahir","family":"Kota","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7078-2069","authenticated-orcid":false,"given":"Abdul Ahad Ghaffar","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3411-9125","authenticated-orcid":false,"given":"Mohammed","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0217-8270","authenticated-orcid":false,"given":"Samuel Ebele","family":"Udeabor","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abosofyan Salih Atta Elfadeel Mohamed","family":"Salih","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chidozie Ifechi","family":"Onwuka","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, King Khalid University, Abha 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","first-page":"153","article-title":"Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions","volume":"22","author":"Pearson","year":"2001","journal-title":"Endocr. 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