{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T21:48:59Z","timestamp":1771710539727,"version":"3.50.1"},"reference-count":65,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T00:00:00Z","timestamp":1708300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\/MCTES","award":["UIDB\/50006\/2020"],"award-info":[{"award-number":["UIDB\/50006\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Recent research has uncovered a promising approach to addressing the growing global health concern of obesity and related disorders. The inhibition of inositol hexakisphosphate kinase 1 (IP6K1) has emerged as a potential therapeutic strategy. This study employs multiple ligand-based in silico modeling techniques to investigate the structural requirements for benzisoxazole derivatives as IP6K1 inhibitors. Firstly, we developed linear 2D Quantitative Structure\u2013Activity Relationship (2D-QSAR) models to ensure both their mechanistic interpretability and predictive accuracy. Then, ligand-based pharmacophore modeling was performed to identify the essential features responsible for the compounds\u2019 high activity. To gain insights into the 3D requirements for enhanced potency against the IP6K1 enzyme, we employed multiple alignment techniques to set up 3D-QSAR models. Given the absence of an available X-ray crystal structure for IP6K1, a reliable homology model for the enzyme was developed and structurally validated in order to perform structure-based analyses on the selected dataset compounds. Finally, molecular dynamic simulations, using the docked poses of these compounds, provided further insights. Our findings consistently supported the mechanistic interpretations derived from both ligand-based and structure-based analyses. This study offers valuable guidance on the design of novel IP6K1 inhibitors. Importantly, our work exclusively relies on non-commercial software packages, ensuring accessibility for reproducing the reported models.<\/jats:p>","DOI":"10.3390\/ph17020263","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T10:40:15Z","timestamp":1708339215000},"page":"263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Shaping the Future of Obesity Treatment: In Silico Multi-Modeling of IP6K1 Inhibitors for Obesity and Metabolic Dysfunction"],"prefix":"10.3390","volume":"17","author":[{"given":"Ismail","family":"Mondal","sequence":"first","affiliation":[{"name":"Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Dr. Meghnad Saha Sarani, Bidhannagar, Durgapur 713206, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4818-9047","authenticated-orcid":false,"given":"Amit Kumar","family":"Halder","sequence":"additional","affiliation":[{"name":"Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Dr. Meghnad Saha Sarani, Bidhannagar, Durgapur 713206, India"},{"name":"LAQV@REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"given":"Nirupam","family":"Pattanayak","sequence":"additional","affiliation":[{"name":"Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Dr. Meghnad Saha Sarani, Bidhannagar, Durgapur 713206, India"}]},{"given":"Sudip Kumar","family":"Mandal","sequence":"additional","affiliation":[{"name":"Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Dr. Meghnad Saha Sarani, Bidhannagar, Durgapur 713206, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3375-8670","authenticated-orcid":false,"given":"Maria Natalia D. S.","family":"Cordeiro","sequence":"additional","affiliation":[{"name":"LAQV@REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1056\/NEJMoa1503840","article-title":"Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood","volume":"374","author":"Twig","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_2","first-page":"201","article-title":"Anti-obesity drug discovery: Advances and challenges","volume":"21","author":"DiMarchi","year":"2021","journal-title":"Nat. Rev. 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