{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:53:17Z","timestamp":1778626397638,"version":"3.51.4"},"reference-count":74,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Overexpression of phosphodiesterase 5 (PDE-5) presents a compelling target for the therapy of erectile dysfunction. Sildenafil and other conventional PDE-5 inhibitors may lead to adverse effects, including visual disturbances and migraines. Therefore, the investigation of novel inhibitors with enhanced safety profiles is imperative. This research employed a computational drug repurposing approach to assess US-FDA-approved xanthine derivatives (XDs) for their efficacy in targeting PDE-5. XDs exhibit a favorable affinity for the active site of the PDE-5 receptor, with binding scores between \u221210.0 kcal\/mol and \u22126.3 kcal\/mol for linagliptin and theobromine, respectively. The top-ranked docked Xds then underwent 300-nanosecond molecular dynamics simulations. Linagliptin demonstrated greater stability in the binding pocket (RMSD\u2009=\u20091.60\u2009\u00b1\u20090.34) compared to the typical inhibitor sildenafil (RMSD\u2009=\u20091.70\u2009\u00b1\u20090.27). The findings were corroborated by MM-PBSA calculation, which showed that linagliptin\u2019s binding free energy of \u221245.6\u2009\u00b1\u20094.3 kcal\/mol comparable with sildenafil\u2019s \u221249.0\u2009\u00b1\u20093.1 kcal\/mol. This value is notably higher than that of the deprotonated form of sildenafil, which is present at a 37.06% ratio at physiological pH 7.4. Additionally, we used per-residue energy decomposition to identify crucial residues for PDE-5 activity and thoroughly investigated hydrogen bond occupancy. This study points outthe potential of linagliptin as a PDE-5 inhibitor, paving the way for the development of a safe treatment for erectile dysfunction.<\/jats:p>","DOI":"10.1371\/journal.pone.0336267","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T18:27:43Z","timestamp":1763058463000},"page":"e0336267","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unveiling of phosphodiesterase-5 hot residues binding to xanthine derivatives for erectile dysfunction therapy: A computational drug repurposing approach"],"prefix":"10.1371","volume":"20","author":[{"given":"Amin O.","family":"Elzupir","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4941-7192","authenticated-orcid":true,"given":"Sondos A. 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