Studi In Silico Potensi Inhibisi Senyawa Aktif Temu Hitam (Curcuma aeruginosa Roxb.) Terhadap Aktivitas Enzim Histon Deasetilase 8 (HDAC8)

Abstract

Leukemia mieloid akut inv(16) terjadi akibat inversi kromosom 16 sehingga membentuk kompleks CBFβ-SMMHC dan menginaktivasi tumor supresor p53 karena deasetilasi berlebihan yang dilakukan enzim histon deasetilase 8 (HDAC8). Penambatan molekuler dilakukan dari senyawa aktif temu hitam (Curcuma aeruginosa Roxb.) terhadap enzim HDAC8 untuk melihat potensi penghambatannya berdasarkan interaksi molekuler ligan dengan reseptor. Penelitian ini bertujuan menentukan potensi inhibisi senyawa aktif temu hitam terhadap enzim HDAC8 melalui parameter energi pengikatan (ΔG), konstanta inhibisi (Ki), kesamaan residu, jenis ikatan, dan jenis inhibisi melalui penambatan molekuler. Potensi paling baik dimiliki oleh demetoksikurkumin (ΔG -6.5 kkal/mol dengan Ki 16.989 µM) dan valerenol (ΔG -6.1 kkal/mol dengan Ki 33.397 µM) dengan nilai persentase BSS masing-masing secara berturut-turut sebesar 77.78% dan 88.89%. Gugus oksigen karbonil dari kedua molekul membentuk ikatan hidrogen dengan residu katalitik Tyr306 sehingga memiliki inhibisi kompetitif.

Acute myeloid leukemia inv(16) is caused by the inversion of chromosome 16 resulting in chimeric protein fusion of CBFβ-SMMHC that deactivates tumor suppressor p53 due to the aberrant deacetylation done by histone deacetylase 8 (HDAC8). Molecular docking was conducted from the active components of temu hitam (Curcuma aeruginosa Roxb.) towards HDAC8 enzyme to see the potential inhibition based on the molecular interaction between ligands and receptor. This study aimed to determine the inhibitory potential of active compounds in temu hitam as potential inhibitors towards HDAC8 enzyme activity through in silico studies using binding free energy score (ΔG), inhibition constant (Ki), residues similarity, type of bonds, and type of inhibition as the parameters. Demethoxycurcumin (ΔG -6.5 kcal/mol and Ki 16.989 µM) and valerenol (ΔG -6.1 kcal/mol and Ki 33.397 µM) showed the best inhibition potential for HDAC8 with %BSS of 77.78% and 88.89%, respectively. Oxygen carbonyl moiety from both molecules create hydrogen bonds with the catalytic machinery residue of Tyr306, thus possessed the competitive inhibition mechanism.