ANALYSIS OF QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP, PHARMACOPHORE, AND MOLECULAR DOCKING OF TETRACYCLIC INDENOQUINOLINE DERIVATIVES AS ANTICANCER AGENTS
Topoisomerases have been the focus in the treatment of some diseases, such as bacterial gyrase (topoisomerase II) and topoisomerase IV which are the targets of two classes of antibiotic drugs: quinolones and coumarins; as well as, Topoisomerase I and topoisomerase II in cancer treatment. QSAR ana...
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| 格式: | Theses |
| 語言: | Indonesia |
| 在線閱讀: | https://digilib.itb.ac.id/gdl/view/45797 |
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| 機構: | Institut Teknologi Bandung |
| 語言: | Indonesia |
| 總結: | Topoisomerases have been the focus in the treatment of some diseases, such as
bacterial gyrase (topoisomerase II) and topoisomerase IV which are the targets of
two classes of antibiotic drugs: quinolones and coumarins; as well as,
Topoisomerase I and topoisomerase II in cancer treatment. QSAR analysis have
been performed on tetracyclic indenoquinoline derivatives as anticancer agents in
three cell lines (HeLa, A-549, and MCF-7 cells). Molecular modelling was
performed by Hyperchem 8.02 package, while the calculation of descriptors used
Molecular Operating Environment (MOE). Statistical analysis was done using
SPSS 17.0 with parameters of r, r
2
, SE, and F. Validation of the equations used
Leave-One-Out Cross Validation with parameters of q
2
. Pharmacophore series of
compounds were explored using the MOE package. Ligand interaction analysis
was performed by docking the derivatives against topoisomerase I receptor.
Furthermore, the design of new derivatives and their activity prediction were
based on the result of QSAR analysis and their interaction using MOE software.
The result showed that physicochemical properties of tetracyclin indenoquinoline
which correlate to the growth inhibition of HeLa are globularity, energy total, heat
of formation, electronic energy, and LUMO energy. For A-549 cells, the
physicochemical properties which play an important role are the partition
coefficient (Log P), globularity, electronic energy, LUMO energy,and total
energy. As for MCF-7 cells, the physicochemical properties related to the activity
is volume, LUMO energy, total hydrophobic surface area, HOMO energy, and
molecular refractivity. Pharmacophore feature of tetracyclin indenoquinoline was
shown by the aromatic group of compound and an electron acceptor. Studies of
interaction indicated that the hydrogen binding interactions play an important role
in increasing the biological activity of the compounds. Design of new derivatives
resulted in 10 compounds that have better predicted biological activity than that of
analogous compounds (camphtetocine) and the test compounds.
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