2026-09-19T06:37:20.109789200Zhttps://opus.uleth.ca/server/oai/requestoai:opus.uleth.ca:10133/62132022-08-04T19:14:54Zcom_10133_3346com_10133_1com_10133_296col_10133_3347col_10133_298
ULethbridge OPUS Repository
supervisor
Thakor, Nehal
supervisor
Wetmore, Stacey D.
author
Chukka, Prakash Amruth Raj
2022-05-27T17:23:36Z
2022-05-27T17:23:36Z
2021
https://hdl.handle.net/10133/6213
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.
en_CA
mRNA translation
uORF
Glioblastoma
Docking
Protein modeling
Antineoplastic drugs
Combined experimental and computational studies of the interactions between small molecule ligands and eukaryotic translation initiation factors eIF5B and eIF4E
Thesis
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
URL
http://localhost:4000/bitstreams/0503d5c4-cd00-405a-84b9-c2afdbd0b663/download
File
MD5
59a13db970eaf00b6aa1cc7609149770
21033409
application/pdf
CHUKKA_PRAKASH_MSC_2022.pdf
URL
http://localhost:4000/bitstreams/7b323807-859f-479e-9c6c-01f6f6c44991/download
File
MD5
2082366fab7a06e0ef4e8ef67d4ab3e2
249251
text/plain
CHUKKA_PRAKASH_MSC_2022.pdf.txt