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Results: The optimal 3D-QSAR model, developed using partial least squares (PLS) and Comparative Molecular Similarity Indices Analysis (CoMSIA), demonstrated strong correlation and predictive power (Q\u00b2=0.541, R\u00b2=0.973, SEE=0.076). ADMET analysis showed that the designed ligands possess acceptable pharmacokinetic and toxicological profiles, supporting their potential for further drug development. Molecular docking revealed that the designed ligands effectively interacted with the active site of \u03b1-amylase (PDB ID: 7TAA). Furthermore, molecular dynamics simulations (100 ns) and MM-PBSA free energy calculations confirmed the stability of ligand-enzyme complexes. Ligand transport was further examined using the CaverDock program, tracking the movement of molecules from the enzyme\u2019s active site to its surface. Finally, retrosynthetic analysis was performed to propose feasible synthesis routes for the most active compound. Conclusion: Overall, the findings highlight a promising lead compound for further in vitro and in vivo investigations targeting \u03b1-amylase inhibition.<\/jats:p>","DOI":"10.34172\/bi.32900","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:32:04Z","timestamp":1789489924000},"page":"32900","update-policy":"https:\/\/doi.org\/10.34172\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An integrative computational strategy for antidiabetic drug discovery: From QSAR modeling to retrosynthesis"],"prefix":"10.34172","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2781-2970","authenticated-orcid":true,"given":"Lhoucine","family":"Naanaai","sequence":"first","affiliation":[{"name":"Laboratory of Processes, Materials, and Environment (LPME), Faculty of Science and Technology, Sidi Mohamed Ben Abdellah University, Fez, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Alaqarbeh","sequence":"additional","affiliation":[{"name":"Applied Science Research Center, Applied Science Private University, Amman, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdellah","family":"El Aissouq","sequence":"additional","affiliation":[{"name":"Laboratory of Processes, Materials, and Environment (LPME), Faculty of Science and Technology, Sidi Mohamed Ben Abdellah University, Fez, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hicham","family":"Zaitan","sequence":"additional","affiliation":[{"name":"Laboratory of Processes, Materials, and Environment (LPME), Faculty of Science and Technology, Sidi Mohamed Ben Abdellah University, Fez, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Bouachrine","sequence":"additional","affiliation":[{"name":"Molecular Chemistry and Natural Substances Laboratory, Faculty of Sciences, Moulay Ismail University, Meknes, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fouad","family":"Khalil","sequence":"additional","affiliation":[{"name":"Laboratory of Processes, Materials, and Environment (LPME), Faculty of Science and Technology, Sidi Mohamed Ben Abdellah University, Fez, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"20123","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/926713"},{"key":"R2","doi-asserted-by":"crossref","unstructured":"Wolde HF, Atsedeweyen A, Jember A, Awoke T, Mequanent M, Tsegaye AT, et al. 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