HUBUNGAN KUANTITATIF STRUKTUR-AKTIVITAS TURUNAN 2- FENILPIRIMIDIN-4-AMIN SEBAGAI SENYAWA ANTIKANKER
Cancer is one of common causes leading to death worldwide. In 2012, lung cancer was responsible for 30% of death from overall cancer. 2-Phenylpyrimidin-4-amine has anticancer activity by catalyzing the removal of ubiquitin from modified proteins, whereas dysfunction in ubiquitin-dependent signali...
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| Format: | Final Project |
| Language: | Indonesia |
| Online Access: | https://digilib.itb.ac.id/gdl/view/45427 |
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| Institution: | Institut Teknologi Bandung |
| Language: | Indonesia |
| Summary: | Cancer is one of common causes leading to death worldwide. In 2012, lung cancer was
responsible for 30% of death from overall cancer. 2-Phenylpyrimidin-4-amine has
anticancer activity by catalyzing the removal of ubiquitin from modified proteins, whereas
dysfunction in ubiquitin-dependent signaling pathways has been linked to various human
diseases, especially cancer. The research was aimed to determine the best Quantitative
Structure-Activity Relationship (QSAR) equation, in order to obtain new derivatives
with higher inhibition activity than that of the parent compound in non-small cell lung
cancer cells (NSCLC). Modeling and optimization of the geometry structure were
done by Gaussian. Calculation of predictor’s value and multilinear statistical analysis
were performed by MOE 2009.10 and SPSS Statistics 16.0, respectively, and the results
were validated by Leave One Out method. The designs of new derivatives were made
according to the Topliss scheme. The new derivates with the higher inhibition activity
were docked to the monoubiquitinated Proliferating Cell Nuclear Antigen (Ub-PCNA) to
observe their affinity based on energy value using Autodock 4.2.5.1. The best QSAR
equation of 2-phenylpyrimidin-4-amine derivatives is log IC50 (µM) = 0.135(±0.330) ?
0.014(±8.213x10
?3
) x (AM1_HF) ?2.071(±1.125) x (AM1_LUMO) ?3.731(±0.090) x
(log P) ?2.578(±0.056) x (log S). The QSAR equation which is influenced by the heat
formation, Lowest Unoccupied Molecular Orbital (LUMO) energy, logarithm of
lipophilicity (partition coefficient), and logarithm of the solubility was used to design 24
new derivatives. It has been found that 24 new compounds have IC50 lower than that of the
parent compound. Two of them have been proven having higher affinity to the Ub-PCNA
receptor due to its number of hydrogen bond, amino acid residue, binding energy, and
inhibition constant.
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