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Enhanced PL activity promotes excessive lipid assimilation and contributes to positive energy balance, key pathophysiological mechanisms underlying the escalating global prevalence of obesity\u2014a complex, multifactorial condition strongly associated with metabolic disorders, including type 2 diabetes mellitus and cardiovascular disease. Inhibition of pancreatic lipase (PL) constitutes a well-established therapeutic approach for attenuating dietary lipid absorption and mitigating obesity. Methods: With the aim to identify putative PL inhibitors, a Structure-Based Virtual Screening (SBVS) of PhytoHub database naturally occurring derivatives was performed. A refined library of 10,404 phytochemicals was virtually screened against a crystal structure of pancreatic lipase. Candidates were filtered out based on binding affinity, Lipinski\u2019s Rule of Five, and structural clustering, resulting in six lead compounds. Results: In vitro, enzymatic assays confirmed theoretical suggestions, highlighting Pinoresinol as the best PL inhibitor. Molecular dynamics simulations, performed to investigate the stability of protein\u2013ligand complexes, revealed key interactions, such as persistent hydrogen bonding to catalytic residues. Conclusions: This integrative computational\u2013experimental workflow highlighted new promising natural PL inhibitors, laying the foundation for future development of safe, plant-derived anti-obesity therapeutics.<\/jats:p>","DOI":"10.3390\/ph18091246","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T13:47:49Z","timestamp":1755870469000},"page":"1246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Leveraging Natural Compounds for Pancreatic Lipase Inhibition via Virtual Screening"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3655-3696","authenticated-orcid":false,"given":"Emanuele Liborio","family":"Citriniti","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Della Salute, Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0680-7097","authenticated-orcid":false,"given":"Roberta","family":"Rocca","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Della Salute, Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science S.r.l., Universit\u00e0 \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Associazione CRISEA\u2014Centro di Ricerca e Servizi Avanzati per l\u2019Innovazione Rurale, Localit\u00e0 Condoleo di Belcastro, 88055 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1043-9562","authenticated-orcid":false,"given":"Claudia","family":"Sciacca","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Chimiche, Universit\u00e0 Degli Studi di Catania, V.le A. Doria 6, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1480-0861","authenticated-orcid":false,"given":"Nunzio","family":"Cardullo","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Chimiche, Universit\u00e0 Degli Studi di Catania, V.le A. Doria 6, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6212-5154","authenticated-orcid":false,"given":"Vera","family":"Muccilli","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Chimiche, Universit\u00e0 Degli Studi di Catania, V.le A. 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