{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:14:25Z","timestamp":1775542465992,"version":"3.50.1"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"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. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                      lung infections are difficult to eradicate because of biofilms and rising resistance. MraY (MRAY_PSEAE), an essential membrane enzyme in peptidoglycan biosynthesis, depends on divalent metals (notably Mg\n                      <jats:sup>2+<\/jats:sup>\n                      ); therefore, metal coordination is critical for reliable structure-based prioritization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We built an explicit protein\u2013ligand\u2013metal model of MRAY_PSEAE and extracted pocket constraints from point-cloud geometry and polar\/charged features. Candidates were generated through similarity-guided library expansion, combining PubChem 2D similarity retrieval with local rule-based BRICS enumeration. After canonicalization and 2D\/property filtering, compounds were clustered by fingerprint similarity and prioritized through chemical-state plausibility, docking, Prime\/MM-GBSA rescoring, and ligand strain filtering, followed by interaction analysis, 1-\u03bcs MD, and\n                      <jats:italic>in silico<\/jats:italic>\n                      ADMET.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Three hits (6675, 2733768, 5311309) were prioritized. In microsecond MD, compound 5311309 showed the most stable pose and key hotspot retention. ADMET indicated a permeability\/efflux bottleneck along with liver\u2013kidney and irritation\/sensitization alerts, whereas hERG and AMES signals were favorable. In growth assays, compound 5311309 showed an IC50 of approximately 15.1\u202f\u03bcM and an MIC of 64\u202f\u03bcM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Metal-aware pocket modeling plus multi-level screening improved plausibility and ranking for this metal-dependent target, identifying compound 5311309 as a practical lead optimization starting point.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1798540","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:33:54Z","timestamp":1775540034000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A metal-aware library-expansion and virtual-screening workflow for Pseudomonas aeruginosa ATCC 15692 (PAO1) MraY identifies compound 5311309 with stable binding and mid-micromolar activity"],"prefix":"10.3389","volume":"17","author":[{"given":"Tao","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lichen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Jiangnan University","place":["Wuxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengnan","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He","family":"Zhengfu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1080\/17425255.2022.2113380","article-title":"The role of OATP1B1 and OATP1B3 transporter polymorphisms in drug disposition and response to anticancer drugs: a review of the recent literature","volume":"18","author":"Anabtawi","year":"2022","journal-title":"Expert Opin. 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