Background:
The abnormal signaling from tyrosine kinase causes many types of cancers namely breast cancer,
non-small cell lung cancer, and chronic myeloid leukemia. This research reports the in-silico, synthesis, and in-vitro study
of novel pyrimidine derivatives as EGFR inhibitors.
Objective:
The objective of the research study is to discover more promising lead compounds using drug discovery
process, in which the rational drug design is achieved by the molecular docking and virtual pharmacokinetic studies.
Methods:
The molecular docking studies were carried out using discovery studio 3.5-version software. The molecules
with good docking and binding energy score were synthesized as well as their structures were confirmed by FT-IR, NMR,
Mass and elemental analysis. Subsequently molecules were evaluated for their anticancer activity using MDA-MB-231,
MCF-7 and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology.
Results:
Pyrimidine derivatives displayed anticancer activity. Particularly, compound R8 shows significant cytotoxicity
against MDA-MB-231 with an IC50 18.5 ± 0.6 µM. Molecular docking studies proved that the compound R8 has good
binding fitting by forming hydrogen bonds with amino acid residues at ATP binding sites of EGFR.
Conclusion:
Eight pyrimidine derivatives were designed, synthesized and evaluated against breast cancer cell lines.
Compound R8 significantly inhibited the growth of MDA-MB-231 and MCF-7. Molecular docking studies reveled that
compound R8 has good fitting by forming different Hydrogen bonding interactions with amino acids at ATP binding site
of epidermal growth factor receptor target. Compound R8 was a promising lead molecule that showed better results as
compared to other compounds in in-vitro studies.
In silico pharmacokinetic and molecular docking studies of small molecules derived from Indigofera aspalathoides Vahl targeting receptor tyrosine kinases
