{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:48:15Z","timestamp":1790995695565,"version":"4.1.0"},"reference-count":59,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Propranolol is a non-selective \u03b2-adrenergic receptor antagonist widely used in cardiovascular and neurological therapy. Its naphthalene-based structure contributes to its high lipophilicityand central nervous system penetration. Clinically, propranolol is indicated for hypertension, arrhythmias, anxiety, migraine, and other conditions. It undergoes extensive hepatic metabolism via cytochrome P450 enzymes, notably CYP2D6, with a significant first-pass effect limiting oral bioavailability. This review integrates pharmacological profiling with crystallographic analysis to explore propranolol\u2019s molecular interactions and therapeutic versatility. High-resolution crystal structures of the human \u03b22-adrenergic receptor (h\u03b22-AR), particularly PDB ID: 6PS5 obtained via serial femtosecond crystallography (SFX), reveal key binding determinants responsible for receptor affinity and antagonism. Comparative structural analysis with other \u03b2-blockers\u2014alprenolol, timolol, and carvedilol\u2014highlights how variations in aromatic and heterocyclic frameworks influence pharmacokinetics and receptor selectivity. Superimposition results (RMSD: 0.032 for propranolol\u2013alprenolol, 0.078 for propranolol\u2013carvedilol, and 1.078 for propranolol\u2013timolol) quantitatively illustrate molecular similarity and divergence. The enantioselective behavior of propranolol is also discussed, with the S-enantiomer showing greater receptor affinity and pharmacological potency than the R-form. Beyond canonical \u03b2-adrenergic targets, propranolol interacts with non-canonical proteins such as the cellulase enzyme Cel7A and lactoferrin, suggesting off-target effects and novel therapeutic potential. These findings underscore the importance of propranolol\u2019s amphiphilic character, stereochemistry, and electrostatic properties in shaping its pharmacological profile. Overall, the integration of crystallographic data with pharmacological insights supports the rational design of next-generation \u03b2-adrenergic ligands with enhanced selectivity, bioavailability, and clinical efficacy.<\/jats:p>","DOI":"10.3390\/ijms262010080","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T12:17:02Z","timestamp":1760617022000},"page":"10080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structural and Pharmacological Insights into Propranolol: An Integrated Crystallographic Perspective"],"prefix":"10.3390","volume":"26","author":[{"given":"Adrianna","family":"Witczy\u0144ska","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Toru\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6778-8259","authenticated-orcid":false,"given":"\u0141ukasz","family":"Fija\u0142kowski","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Toru\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6294-3256","authenticated-orcid":false,"given":"Dagmara","family":"Mirowska-Guzel","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Centre for Preclinical Research and Technology, Banacha 1b, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Blecharz-Klin","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Centre for Preclinical Research and Technology, Banacha 1b, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4945-2369","authenticated-orcid":false,"given":"Alicja","family":"Nowaczyk","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 87-100 Toru\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4103\/aian.AIAN_201_18","article-title":"Propranolol: A 50-year historical perspective","volume":"22","author":"Srinivasan","year":"2019","journal-title":"Ann. 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