{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:02:22Z","timestamp":1789578142797,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011093","name":"School of Medicine, University of Phayao","doi-asserted-by":"publisher","award":["MD69-13"],"award-info":[{"award-number":["MD69-13"]}],"id":[{"id":"10.13039\/501100011093","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011093","name":"School of Medicine, University of Phayao","doi-asserted-by":"publisher","award":["MD69-14"],"award-info":[{"award-number":["MD69-14"]}],"id":[{"id":"10.13039\/501100011093","id-type":"DOI","asserted-by":"publisher"}]},{"award":["MD69-13"],"award-info":[{"award-number":["MD69-13"]}],"id":[{"id":"https:\/\/ror.org\/00a5mh069","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MD69-14"],"award-info":[{"award-number":["MD69-14"]}],"id":[{"id":"https:\/\/ror.org\/00a5mh069","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002842","name":"Chiang Mai University","doi-asserted-by":"publisher","award":["11\/2025"],"award-info":[{"award-number":["11\/2025"]}],"id":[{"id":"10.13039\/501100002842","id-type":"DOI","asserted-by":"publisher"}]},{"award":["11\/2025"],"award-info":[{"award-number":["11\/2025"]}],"id":[{"id":"https:\/\/ror.org\/05m2fqn25","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Osteoporosis is a prevalent skeletal disorder characterized by excessive bone resorption and an increased risk of fragility fracture. Cathepsin K (CatK), a lysosomal cysteine protease predominantly expressed in osteoclasts, is an established target for anti-resorptive drug development. Here, an integrated computational workflow comprising virtual screening, molecular docking, 300 ns molecular dynamics (MD) simulations, molecular mechanics\/Poisson\u2013Boltzmann surface area (MM\/PBSA) calculations, and drug-likeness\/ADMET prediction was used to prioritize natural product-derived CatK ligands from the MEGxM database. Among approximately 6500 screened compounds, TOP1 (PubChem ID: 97043052) and TOP2 (PubChem ID: 135765825) showed docking scores of \u22128.2 and \u22127.8 kcal\/mol, respectively, compared with \u22126.6 kcal\/mol for the comparative reference ligand (STD). Both compounds satisfied Lipinski\u2019s rule of five; however, their predicted ADMET profiles were mixed, including negative predictions for human intestinal absorption for both compounds and compound-specific metabolic and toxicity liabilities. The 300 ns MD trajectories indicated broadly stable CatK ligand complexes. TOP1 showed slightly lower mean RMSD)\/RMSF values than TOP2. In contrast, TOP2 exhibited more favorable MM\/PBSA binding free energies than TOP1 at both analyzed intervals (\u221283.45 \u00b1 10.06 and \u221280.74 \u00b1 10.18 kJ\/mol for TOP2 versus \u221274.28 \u00b1 10.08 and \u221257.21 \u00b1 15.04 kJ\/mol for TOP1), while STD showed the most favorable MM\/PBSA binding free energies overall. Collectively, TOP1 and TOP2 exhibited complementary computational profiles and should therefore be regarded as candidates for biochemical and cellular validation rather than confirmed CatK inhibitors or orally suitable drug leads.<\/jats:p>","DOI":"10.3390\/ijms27188258","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:07:29Z","timestamp":1789574849000},"page":"8258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Virtual Screening and Molecular Dynamics Simulations Identifying Natural Product-Derived Cathepsin K Inhibitors as Potential Therapeutics for Osteoporosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Thitinun","family":"Tarathipayakul","sequence":"first","affiliation":[{"name":"Department of Orthopedic, School of Medicine, University of Phayao, Phayao 56000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuvaraj","family":"Ravikumar","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, School of Sciences and Humanities, SR University, Warangal 506371, India"},{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pattaranee","family":"Srichairatanakool","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, School of Medicine, University of Phayao, Phayao 56000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jittasak","family":"Khowsathit","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5706-8781","authenticated-orcid":false,"given":"Somdet","family":"Srichairatanakool","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/s11657-020-00871-9","article-title":"SCOPE 2021: A new scorecard for osteoporosis in Europe","volume":"16","author":"Kanis","year":"2021","journal-title":"Arch. 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