الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression causes various types of
cancers like breast, ovary, gastric, endometrium, bladder, lung, colon, and head and neck. So,
small molecule tyrosine kinase inhibitors are appealing therapeutic targets because they can
suppress cell signaling associated with many of the suggested HER2 cancers. Despite recently
approved drugs, several resistance mechanisms have been identified. Therefore, there is a
need to enhance drug binding to HER2 to block signalling pathways.
The present study planned to define the structural basis required to selectively intervene the
target through rigorous ligand-based and structure-based studies. Using 2D and 3D QSAR to
find out the common features of HER2 modulators, reliable docking algorithms and water
map analysis to define the essential pieces of ligands and amino acids for target modulation.
3D based QSAR results conclude that enhancing HER2 inhibitory activity of the compounds
studied can be mediated by substitution of piperidine and 1,4-diazipine with a hydroxyl
group, primary amine or secondary amine. Also, the activity can be enhanced by the
substitution of the methyl bridge between benzene and indazole ring with hydrophilic polar
substituents. To increase the hydrophobic interaction with the hydrophobic pocket of HER2,
to indazole, 1,4-diazipine or pipredine rings should be substituted with hydrophobic group.
Para substitution of benzene ring, 1,4-diazipine ring and piperidine ring with high
electronegative substituents like oxygen and flour will mediate strong interaction with HER2
receptor.
To sum up the main features of binding interaction, the hydrophobic pocket of Ala771,
Met774 and Leu785 was detected, this interaction was mediated by hydrophobic substituents
on the benzene ring attached to indazole ring. Also, the indazole scaffold mediates interaction
with Leu726, Val734, Ala751 and Ile752.
Most of hydrogen bonds formed were afforded by hydrogen bond donor or acceptor
functional groups that is substitutions on pyrrolo[2,1-f][1,2,4]triazine ring.
Watermap results conclude that water sites at receptor hydrophobic pocket can be either
partially or completely displaced by addition of hydrophobic or halogen (Cl, F or Br)
substitutions to the ligand while that localized on Pyrrolo[3,2-d]pyrimidine ring can be
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Summary and Conclusion
substituted by (polar) functional group. That will aid in the improvement of the binding
affinity and potency of the drug during its development process.