Electronic Theses and Dissertation

Diabetes melitus (dm) merupakan penyakit metabolik dengan prevalensi global yang meningkat. terapi konvensional seringkali disertai efek samping, sehingga eksplorasi senyawa alam seperti flavonoid kaempferol dan rhamnetin sebagai alternatif menarik untuk dikaji. kombinasi kedua senyawa diduga dapat memberikan efek sinergis melalui mekanisme multi-target. penelitian ini bertujuan mengevaluasi mekanisme antidiabetes dan potensi sinergisme kombinasi kaempferol dan rhamnetin secara in silico menggunakan pendekatan network pharmacology dan molecular docking. penelitian ini menggunakan metode identifikasi target gen senyawa menggunakan swisstargetprediction, sedangkan target gen dm diperoleh dari genecards. irisan gen dianalisis dengan venny, dan jejaring protein-protein (ppi) dibangun menggunakan string-db serta dianalisis dengan cytoscape (plugin cytohubba). analisis gene ontology (go) dan kyoto encyclopedia of genes and genomes (kegg) dilakukan untuk mengetahui fungsi biologis dan jalur pensinyalan. validasi afinitas pengikatan terhadap target kunci (α-glukosidase (pdb: 5nn8) dan dpp-4 (pdb: 4a5s)) dilakukan dengan molecular docking menggunakan moe 2010. hasil penelitian ini mengidentifikasi 163 gen target bersama antara kombinasi senyawa dan dm. sepuluh gen kunci (hub genes) antara lain akt1, igf1r, dan esr1, yang terlibat dalam jalur patogenik utama seperti pi3k-akt dan hif-1 signaling. hasil docking menunjukkan kaempferol memiliki afinitas terhadap α-glukosidase (Δg = -12,496 kcal/mol) dan dpp-4 (Δg = -11,427 kcal/mol), dengan pola ikatan pada dpp-4 yang menyerupai obat standar sitagliptin (mengikat glu 205, glu 206, dan tyr 662). rhamnetin menunjukkan afinitas terhadap α-glukosidase (Δg = -11,863 kcal/mol). kedua senyawa mengikat residu katalitik asp 282 pada α-glukosidase. kesimpulan penelitian ini yaitu kombinasi kaempferol dan rhamnetin berpotensi menghasilkan efek antidiabetes sinergis melalui mekanisme multi-target, yaitu penghambatan enzim α-glukosidase dan dpp-4 serta modulasi jejaring gen inti yang terlibat dalam pensinyalan insulin, apoptosis, dan inflamasi. temuan ini memberikan dasar rasional untuk pengembangan terapi kombinasi berbasis senyawa alam.

Diabetes mellitus (DM) is a metabolic disease with a rising global prevalence. Conventional therapies are often accompanied by side effects, making the exploration of natural compounds such as the flavonoids kaempferol and rhamnetin an attractive alternative to investigate. The combination of these two compounds is suspected to have a synergistic effect through multi-target mechanisms. This study aims to evaluate the antidiabetic mechanisms and potential synergy of the combination of kaempferol and rhamnetin through in silico approaches using network pharmacology and molecular docking methods. This research used the SwissTargetPrediction database to identify compound gene targets, while DM gene targets were obtained from GeneCards. Gene intersections were analyzed using Venny, and protein-protein interaction (PPI) networks were constructed using STRING-db and analyzed with Cytoscape (CytoHubba plugin). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to identify biological functions and signaling pathways. Binding affinity validation to key targets (α-Glucosidase (PDB: 5NN8) and DPP-4 (PDB: 4A5S)) was performed via molecular docking using MOE 2010. The results of this study identified 163 shared target genes between the compound combination and DM. Ten hub genes included AKT1, IGF1R, and ESR1, which are involved in key pathogenic pathways such as PI3K-Akt and HIF-1 signaling. Docking results showed that kaempferol has affinity for α-Glucosidase (ΔG = -12.496 kcal/mol) and DPP-4 (ΔG = -11.427 kcal/mol), with a binding pattern on DPP-4 resembling the standard drug Sitagliptin (binding to Glu 205, Glu 206, and Tyr 662). Rhamnetin showed affinity for α-Glucosidase (ΔG = -11.863 kcal/mol). Both compounds bind to the catalytic residue Asp 282 on α-Glucosidase. In conclusion, the combination of kaempferol and rhamnetin has the potential to produce synergistic antidiabetic effects through multi-target mechanisms: inhibition of the enzymes α-Glucosidase and DPP-4, and modulation of core gene networks involved in insulin signaling, apoptosis, and inflammation. These findings provide a rational basis for the development of natural compound-based combination therapies.