In-silico Study of Non-Specific EGFR Inhibitors for Targeting EGFRvIII in Glioblastoma

Abstract

Glioblastoma (GBM) is known to be an extremely aggressive and malignant form of anaplastic arythrocytoma affecting the central nervous system in humans. Due to its worse prognosis leading to high mortality rate over the years , there is an urgent need to deviate from conventional surgical and radiation therapeutic treatments and delve into molecular targeted drug therapy techniques. Epiderma Growth Factor Receptor(EGFR) and its mutant version of EGFRvIII are known to be overexpressed case of GBM resulting in high rate of proliferation and failure in cell cycle arrest. EGFRvIII is expressed in about 62% of GBM cases and are self-activating receptors independent of ligands. This project is undertaken for the study of potential inhibitors for EGFRvIII mutant using bioinformatics tool. Thirteen of commercially available EGFR inhibitors were docked against EGFRvIII protein and stability of the docked results was based on their free binding energy values. The result was compared with that of Gefitinib and Erlotinib, the established inhibitors of EGFR. PD153035, Lavendustin A and BIBX-1328BS were found to be the most suitable inhibitor for EGFRvIII , which can be proposed for wet-lab testing as molecular targeted drug therapy for GBM. Further, few structural modifications on two of these ligands were performed and in-silico docking analysis was repeated to check for more potential alternatives which can prove to be favourable inhibitors.