Skripsi

Studi In Silico Senyawa Aktif Ekstrak Etil Asetat dan n-Heksana Kecombrang (Etlingera elatior) sebagai Agonis PPAR-γ pada Diabetes Melitus Tipe 2 = In Silico Study of Active Compounds from Ethyl Acetate and n-Hexane Extracts of Torch Ginger (Etlingera elatior) as PPAR-γ Agonists in Type 2 Diabetes Mellitus.

Latar Belakang Diabetes mellitus tipe 2 sering berkaitan dengan resistensi insulin dan gangguan metabolisme glukosa–lipid. Aktivasi PPAR-γ meningkatkan sensitivitas insulin sehingga menjadi target terapeutik penting. Kecombrang (Etlingera elatior) mengandung berbagai senyawa bioaktif yang berpotensi sebagai agonis PPAR-γ; studi in silico diperlukan untuk memprediksi afinitas dan profil farmakokinetik sebelum uji biologis lanjut. Metode Penelitian ini bersifat deskriptif-eksploratif dengan pendekatan in silico. Senyawa aktif dari ekstrak etil asetat dan n-heksana kecombrang dianalisis menggunakan metode penambatan molekuler dengan perangkat lunak AutoDock 4.2.6 terhadap protein target PPAR-γ yang telah divalidasi (RMSD < 2 Å). Kompleks dengan afinitas terbaik disimulasikan menggunakan dinamika molekuler (YASARA) untuk menilai kestabilan (RMSD dan RMSF). Profil farmakokinetik dan toksisitas diprediksi menggunakan Lipinski Rule of Five, pkCSM dan ProTox. Hasil Hasil docking menunjukkan nilai energi ikatan berkisar antara −5,06 hingga −10,19 kkal/mol. Tiga senyawa dengan afinitas tertinggi adalah Carbonic acid, but-2-yn-1-yl octadecyl ester (−10,19 kkal/mol), 3-(6-Methyl-3-pyridyl)-5-phenyl-1-(psulfamoylphenyl)-2-pyrazoline (−8,71 kkal/mol), dan Cyclopentane, (4-octyldodecyl)- (−7,95 kkal/mol). Ketiganya berinteraksi dengan residu penting PPAR-γ seperti Arg288, Ser289, Leu330, Phe363, dan Tyr473. Simulasi molecular dynamics menunjukkan kompleks relatif stabil, meskipun beberapa ligan memiliki fleksibilitas tinggi. Analisis ADMET menunjukkan bahwa sebagian besar senyawa memenuhi kriteria drug-likeness, namun beberapa memiliki potensi hepatotoksik dan interaksi dengan enzim CYP. Kesimpulan Senyawa-senyawa dari ekstrak etil asetat dan n-heksan kecombrang menunjukkan potensi sebagai modulator selektif PPAR-γ dengan afinitas pengikatan yang menjanjikan dan profil in silico yang mengindikasikan kemungkinan aktivitas partial agonist. Namun, beberapa kandidat menampilkan isu farmakokinetik (lipofilisitas tinggi, potensi interaksi CYP, risiko hepatotoksisitas) sehingga direkomendasikan uji biologis in vitro/in vivo dan optimasi formulasi sebelum pengembangan lebih lanjut.
Kata Kunci: Etlingera elatior, kecombrang, PPAR-γ, penambatan molekuler, dinamika molekuler, ADMET.


Introduction Type 2 diabetes mellitus is a chronic metabolic disorder characterized by insulin resistance and impaired glucose and lipid metabolism. Activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a key role in improving insulin sensitivity. Etlingera elatior (torch ginger) contains various bioactive compounds that potentially act as PPAR-γ agonists. Therefore, in silico studies are essential to predict their binding affinity and pharmacokinetic profiles prior to further biological evaluation. Method This descriptive-exploratory research employed an in silico approach. Active compounds from ethyl acetate and n-hexane extracts of Etlingera elatior were analyzed using molecular docking with AutoDock 4.2.6 against a validated PPAR-γ structure (RMSD < 2 Å). The best docked complexes were further evaluated through molecular dynamics simulation using YASARA to assess their stability based on RMSD and RMSF values. Pharmacokinetic and toxicity properties were predicted using pkCSM and ProTox 3.0 following Lipinski’s Rule of Five. Results Docking analysis revealed binding energies ranging from −5.06 to −10.19 kcal/mol. The top three ligands with the highest affinity were Carbonic acid, but-2-yn-1 -yl octadecyl ester (−10.19 kcal/mol), 3-(6-Methyl-3-pyridyl)-5-phenyl-1 -(p-sulfamoylphenyl)-2- pyrazoline (−8.71 kcal/mol), and Cyclopentane, (4-octyldodecyl)- (−7.95 kcal/mol). These ligands interacted with key PPAR-γ residues such as Arg288, Ser289, Leu330, Phe363, and Tyr473. Molecular dynamics simulations indicated that the complexes were relatively stable, though several ligands exhibited higher flexibility. ADMET analysis showed that most compounds met the drug-likeness criteria, yet some displayed potential hepatotoxicity and CYP enzyme inhibition risks. Conclusion Active compounds from Etlingera elatior ethyl acetate and n-hexane extracts demonstrated promising potential as selective PPAR-γ modulators with favorable binding affinities and stable complex formation. Nevertheless, further in vitro and in vivo studies, along with formulation optimization, are required to overcome pharmacokinetic and toxicity limitations identified in in silico evaluations.
Keywords: Etlingera elatior, PPAR-γ, in silico, molecular docking, molecular dynamics, ADMET.