Combined experimental and computational studies of the interactions between small molecule ligands and eukaryotic translation initiation factors eIF5B and eIF4E
Chukka, Prakash Amruth Raj
Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry
eIF5B and eIF4E are aberrantly expressed in several cancers, and there is a growing body of literature that recognises their importance in cancer survival. This thesis attempts to study the interactions of small molecule inhibitors with eIF5B and eIF4E by combining cell, molecular, and computational biology techniques. Through western blotting, we identified that ribavirin does not affect the function of eIF5B in BT48 and U343 cells. These results were corroborated by MD simulations, which suggested that the charge on nucleobase of RTP prevents interaction with eIF5B. Using homology modeling and protein validation, the first human eIF5B structure was generated that facilitated the identification of the LWW31 binding site. In addition, MD simulations provided insights into the stability of m7GTP and the binding mode of RBV. Overall, this thesis provides insight into small molecule interactions with eIF5B and eIF4E, which might be beneficial for the future drug design of antineoplastic drugs.
mRNA translation , uORF , Glioblastoma , Docking , Protein modeling , Antineoplastic drugs