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A promising strategy for developing effective anti-obesity agents is to inhibit pancreatic lipase, thereby reducing lipid absorption. Currently, the only clinically approved pharmacological agent for pancreatic lipase inhibition is Orlistat. However, its undesirable gastrointestinal side effects have prompted the search for more effective and potent drugs. This study investigates the inhibitory mechanism of Bromhexine, a mucolytic drug, on pancreatic lipase using Lineweaver\u2013Burk plot analysis and molecular docking, along with simulations, and compares its efficacy to that of the Food and Drug Administration (FDA) approved drug Orlistat. Kinetic analysis indicates that Bromhexine exhibits mixed inhibition of pancreatic lipase, with IC<jats:sub>50<\/jats:sub> and K<jats:sub>i<\/jats:sub> values of 360 \u00b5M and 450 \u00b5M, respectively, which are comparable to those of Orlistat. Molecular docking confirms that Bromhexine interacts with the His263 residue in the enzyme\u2019s active site through hydrogen bonding, similar to Orlistat, thereby reducing the enzyme\u2019s affinity for its natural substrate. Binding pose metadynamics (BPMD) simulations further supports the stability of Bromhexine\u2019s interactions. Collectively, our findings suggest that Bromhexine displays potent pancreatic lipase (PL) inhibition activity and could serve as a potential candidate in weight management as demonstrated by both in silico and in vitro analyses. However, further investigations, including structure-activity relationship (SAR) analyses and in vivo studies, are necessary to confirm its clinical potential as a pancreatic lipase inhibitor.<\/jats:p>","DOI":"10.1038\/s41598-025-02625-4","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T16:09:27Z","timestamp":1748275767000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Combining kinetics and in silico approaches to evaluate bromhexine as an anti-pancreatic lipase agent for obesity management"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8477-3929","authenticated-orcid":false,"given":"Asma","family":"Gholami","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-7324","authenticated-orcid":false,"given":"Dariush","family":"Minai-Tehrani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5654-3109","authenticated-orcid":false,"given":"Leif A.","family":"Eriksson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"issue":"3","key":"2625_CR1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1592\/phco.20.4.270.34882","volume":"20","author":"AM Heck","year":"2000","unstructured":"Heck, A. 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