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Title: Structure-based design of anti-cancer drugs : the use of biophysical techniques for screening and characterization of novel inhibitors of the initiation factor eIF4E
Author: Brown, Christopher John
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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In this work high resolution crystals were produced of full length human eIF4E complexed to m7GTP and the 4E-BP1 motif peptide. The interactions of eIF4E with the cap structure were also analysed by mass spectrometry, revealing a requirement of eIF4E for a guanine monophosphates derivative with a positive delocalised charge on the m7G string. Potential inhibitors for screening were either isolated using virtual screening techniques or synthesised to produce a series of cap mimicking molecules containing a positive delocalised charge. Mass spectrometry identified a series of N7 substituted CMP derivatives that bound to eIF4E in the gas-phase. These compounds were then used in co-crystallisation trials with full length human eIF4E complexed with a 4E-BP1 motif peptide. The co-crystal structures of eIF4E with N7 benzyl derivatives revealed a flipping of the tryptophan 102 to accommodate the bulky N7 group and the expulsion of two structured waters. It also showed that if a para-fluoro group is located on the benzyl modification, then interactions also occur with structured water and an arginine, which explains its increased binding to eIF4E. The flipping of the tryptophan reveals the inherent flexibility in the cap-binding site. The structural information, revealing that the cap-binding site of eIF4E undergoes a conformational change in binding N7 derivatives of GMP with large bulky groups, provides us with valuable insight that can be used in future drug design efforts. The mass spectrometry assay coupled with a clear structure activity relationship, developed on the basis of various “cap-like” ligands studied in the work, gives an excellent starting point for the development of cap-analogue mimics for anti-cancer therapeutics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available