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In Silico Identification of Novel Dipeptidyl Peptidase 4 Inhibitors via Pharmacophore-Guided Virtual Screening.
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Tóm tắt
Dipeptidyl peptidase 4 (DPP4) plays a crucial role in glucose metabolism and is a validated therapeutic target for type 2 diabetes mellitus. Despite the availability of several DPP4 inhibitors, the discovery of novel scaffolds with improved safety and pharmacokinetic profiles remains an unmet need. In this study, a structure-based pharmacophore model integrating key interaction features of saxagliptin and vildagliptin was constructed and applied to screen the Enamine database, aiming to identify new chemotypes distinct from existing inhibitors. The top hits were prioritized through molecular docking, drug-likeness assessment, and ADMET prediction. Among them, compound 3 emerged as a novel lead scaffold, showing strong binding affinity (-9.5 kcal/mol) and stable interactions with critical catalytic residues, including Ser630 and Tyr547. SwissADME analysis indicated favorable oral pharmacokinetics with high gastrointestinal absorption and no BBB penetration. Toxicity prediction suggested low acute toxicity (LD₅₀ = 1500 mg/kg, Class 4), with minimal hepatic and cardiac risks. Overall, this work introduces a computationally validated pharmacophore-driven strategy to identify new DPP4 inhibitor scaffolds, providing a promising starting point for further experimental optimization.
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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Từ khóa
Diabetes mellitus, Dipeptidyl peptidase 4 (DPP4), Pharmacophore model, Computer-aided drug discovery, Molecular docking
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