{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T08:34:18Z","timestamp":1786523658359,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"publisher","award":["QUCP-CAS-2024-365"],"award-info":[{"award-number":["QUCP-CAS-2024-365"]}],"id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"publisher","award":["QUPD-CPH-23\/24-592"],"award-info":[{"award-number":["QUPD-CPH-23\/24-592"]}],"id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"publisher"}]},{"award":["QUCP-CAS-2024-365"],"award-info":[{"award-number":["QUCP-CAS-2024-365"]}],"id":[{"id":"https:\/\/ror.org\/00yhnba62","id-type":"ROR","asserted-by":"publisher"}]},{"award":["QUPD-CPH-23\/24-592"],"award-info":[{"award-number":["QUPD-CPH-23\/24-592"]}],"id":[{"id":"https:\/\/ror.org\/00yhnba62","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Qatar Research Development and Innovation Council","award":["ARG01-0601-230451"],"award-info":[{"award-number":["ARG01-0601-230451"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: The rapid escalation of multidrug-resistant P. aeruginosa necessitates anti-virulence strategies targeting quorum sensing rather than bacterial survival; however, integrating scaffold repurposing with generative AI to inhibit LasR remains underexplored. Here, we address this gap by combining triazole scaffold mining with transformer-based de novo molecular generation to systematically identify putative LasR inhibitors. Methods: An integrated computational pipeline involving Structure-based inhibitor design using Generative Transformer Architecture, deep learning-assisted GNINA rescoring, density functional theory optimization, and molecular dynamics simulations was employed, followed by MM-GBSA binding free energy estimation. Results: Screening of 2666 triazole derivatives and 19,861 DrugGPT-generated compounds yielded top hits with superior binding affinities (\u221211.59 to \u221213.81 kcal\/mol) compared to the reference ligand (\u22128.50 kcal\/mol). MD simulations yielded stable protein\u2013ligand complexes with RMSD values of 2.24\u20133.01 \u00c5, while key interactions involving residues Tyr50, Asp67, and Ser123 were consistently maintained. Binding free energy calculations further confirmed strong thermodynamic stability, with MM-GBSA \u0394Gbind values significantly favorable, supporting robust ligand\u2013receptor affinity. Conclusions: Collectively, these findings establish a powerful AI-integrated framework for anti-virulence drug discovery and identify structurally diverse, high-affinity triazole-based and de novo compounds as promising lead candidates for disrupting LasR-mediated quorum sensing in P. aeruginosa.<\/jats:p>","DOI":"10.3390\/ph19081269","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:30:32Z","timestamp":1786465832000},"page":"1269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combining Triazole Scaffold Repurposing and Generative Transformer Architecture for Structure-Based Inhibitor Design Targeting the LasR Quorum Sensing Receptor of Pseudomonas aeruginosa"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9754-9097","authenticated-orcid":false,"given":"Abbas","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7222-6776","authenticated-orcid":false,"given":"Muhammad Ammar","family":"Zahid","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6318-8707","authenticated-orcid":false,"given":"Anwar","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Precision Health Analysis Unit, Translational Research, Dasman Diabetes Institute, Dasman, Kuwait City P.O. Box 11803, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asia","family":"Al-Jabiry","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-429X","authenticated-orcid":false,"given":"Raed M.","family":"Al-Zoubi","sequence":"additional","affiliation":[{"name":"Surgical Research Section, Department of Surgery, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar"},{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Department of Chemistry, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6748-3663","authenticated-orcid":false,"given":"Mohanad","family":"Shkoor","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2408-552X","authenticated-orcid":false,"given":"Ameera","family":"Al-Jabiry","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8363-1582","authenticated-orcid":false,"given":"Abdelali","family":"Agouni","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41392-022-01056-1","article-title":"Pseudomonas aeruginosa: Pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41579-025-01193-8","article-title":"Pseudomonas aeruginosa: Ecology, evolution, pathogenesis and antimicrobial susceptibility","volume":"23","author":"Letizia","year":"2025","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Nickerson, R., Thornton, C.S., Johnston, B., Lee, A.H., and Cheng, Z. (2024). 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