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Title: Molecular modelling of protein-ligand interactions
Author: Hussain, Abrar
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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In this thesis we discuss the role played by computational methods in drug discovery and present studies chiefly using molecular simulation methodologies to characterise the binding of compounds that may serve as leads for antitumour agents against two separate proteins. We report flexible docking and QSAR studies on aplyronine A, and its analogues, a potent inhibitor of the actin protein system. Our findings delineate the mechanism by which the compounds bind to an actin monomer and highlight key features of the compounds that are fundamental for actin- depolymerisation, which instigates the necessary cytotoxic response. We show that the docking energy scores for the compounds are highly correlated with experimental depolymerisation data. The results are relevant for the design of a putative set of analogues and the development of efficacious actin-targeting cancer drugs. In a second study, we focus on the ETS domain of the Elk-l transcription factor, which is key to the protein's stability and a potential target for therapeutic compounds. The work presented identifies peptide binders of the ETS domain that may be used to inform the design of peptidomimetic compounds. Using MD simulations we show the domain undergoes conformational reorganisation at the α Iβ 1 loop. By taking frames from the MD trajectory of the loop region, we conducted virtual screening experiments for libraries of all possible di- and tri-peptides against each frame. The di- peptides showed no particular preference towards the binding site. However, several tri-peptides made specific interactions with key residues involved in Elk-l dimerisation. Further, we performed peptide-bound dynamics and relative binding free energy simulations to assess the stability of each complex, and to rank more accurately the best binding peptides identified from the docking calculations. We proposed a series of peptide binders for synthesis and experimental binding studies. The thesis ends with a brief discussion on some of the limitations to, and recent advancements in the field of computational modelling, particularly in the realm of atomistic simulations for computer-aided drug discovery.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available