HUBUNGAN KUANTITATIF STRUKTUR-AKTIVITAS (HKSA) TURUNAN 1,5-DIHETEROARILPENTA-1,4-DIEN-3-ON SEBAGAI KANDIDAT SENYAWA ANTIKANKER PROSTAT

• Main Author: Martin
• Format: Final Project
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/44861
• Institution: Institut Teknologi Bandung

Prostate cancer is the fourth most common cancer worldwide, and the second most common cancer in men. Recently, a class of curcumin-based compound (1,5-diheteroaryl-1,4-pentadien-3- ones), has been confirmed to have 17- to 121-fold more potent in inhibiting PC-3 proliferation as compared to curcumin. The aim of the present research was to obtain 1,5-diheteroaryl-1,4- pentadien-3-one derivatives as novel prostate anticancer agents with lower predicted IC50 based on Quantitative Structure-Activity Relationship (QSAR) method and greater affinity to BF-3 and/or W741L mutant Androgen Receptor to prevent drug resistance based on in silico studies. A training set of compounds model was built using GaussView 5.0.8 and optimized by Gaussian 09W. The optimized compounds were computed using MOE 2014.09. Their accuracy were checked through multilinear statistical analysis and validated by Leave One Out (LOO) method using SPSS Statistics 17.0. The best QSAR equation of 1,5-diheteroaryl-1,4-pentadien-3-one derivatives is log IC50 (µM) = 0.261(±0.243) + 0.023(±0.008) AM1_dipole + 0.001(±0.001) ASA_H + 1.971(±0.421) glob ?0.004(±0.001) vol. The Topliss scheme is applied to design new derivatives, and it has been found 27 new derivatives have predicted IC50 lower than that of parent compound ((1E,4E)-1,5- bis(1-isobutyl-1H-benzo[d]imidazol-2-yl)penta-1,4-dien-3-one). AutoDock 4.2.6 was used to dock natural ligand, parent compound, and 27 new derivatives to BF-3 and W741L mutant. The bonding visualization was analyzed using Discovery Studio Visualizer v16.1.0.15350. Two of the new derivatives, compound 44_3 and 44_8, had more negative binding energy and higher affinity toward antagonist region of androgen binding site of W741L mutant, therefore, they could be prostate anticancer agent candidates.