{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:23:53Z","timestamp":1791260633339,"version":"4.1.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"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>Background<\/jats:title>\n                    <jats:p>The therapeutic development of pregnane X receptor (PXR) agonists for ulcerative colitis (UC) is hindered by the poor selectivity of the canonical ligand-binding pocket. This study aimed to identify a novel, selectivity-enhancing binding site on PXR and a corresponding natural ligand for UC treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A distinct binding pocket (Pocket 1\u20135) within the PXR ligand-binding domain was identified using a multi-algorithm computational approach (SiteMap, Fpocket, Prank, CASTpFold). Structure-based virtual screening of 6,058 natural compounds from a traditional Chinese medicine library was performed via Glide docking (High-Throughput Virtual Screening\/Standard Precision\/Extra Precision modes, HTVS\/SP\/XP), with binding affinities refined by molecular mechanics\/generalized Born surface area (MM\/GBSA). The top candidate, TRLW-2 (catechin), was evaluated using luciferase reporter assays, quantitative real-time PCR (Qpcr), and functional assays (CCK-8, EdU, Annexin V-FITC\/PI) in HEK293T and mouse colonic epithelial cells (MCECs).\n                      <jats:italic>In vivo<\/jats:italic>\n                      efficacy was assessed in a DSS-induced murine colitis model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TRLW-2 exhibited high affinity for pocket 1-5, forming key hydrogen bonds with residues including Ser350, Asp352, Asp363, Thr398, and Arg401, which was validated by molecular dynamics simulations (MD) and site-directed mutagenesis. Functionally, TRLW-2 acted as a potent PXR agonist, significantly upregulating detoxifying enzymes (such as Cyp2b10, Cyp3a11 and Ugt1a1) and proliferation markers (PCNA, CDK1, Cyclin B1, and Ki67)\n                      <jats:italic>in vitro<\/jats:italic>\n                      . It promoted epithelial cell proliferation and inhibited apoptosis in MCECs. In DSS-induced colitis mice, TRLW-2 treatment significantly attenuated weight loss, reduced disease activity index DAI) and colonic mucosa damage index (CMDI) scores, ameliorated colon shortening, and improved histopathology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identified pocket 1\u20135 as a selectivity-enhancing site on PXR. The natural product TRLW-2, discovered via virtual screening, potently engages this pocket and demonstrates robust anti-inflammatory and mucosal healing effects, validating a promising strategy for developing precision therapeutics for UC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1726597","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T06:30:59Z","timestamp":1765434659000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting a distinct binding pocket in the pregnane X receptor with natural agonist TRLW-2 ameliorates murine ulcerative colitis"],"prefix":"10.3389","volume":"16","author":[{"given":"Shangrui","family":"Rao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaotang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1053\/j.gastro.2021.04.063","article-title":"Approach to the management of recently diagnosed inflammatory bowel disease patients: a user's guide for adult and pediatric gastroenterologists","volume":"161","author":"Agrawal","year":"2021","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41575-022-00593-y","article-title":"Multiomics to elucidate inflammatory bowel disease risk factors and pathways","volume":"19","author":"Agrawal","year":"2022","journal-title":"Nat. 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