ANALYSIS OF QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP, PHARMACOPHORE, AND MOLECULAR DOCKING OF TETRACYCLIC INDENOQUINOLINE DERIVATIVES AS ANTICANCER AGENTS

• Main Author: Syamsi Dhuha, Nur
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/45797
• Institution: Institut Teknologi Bandung

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.