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Title: Computer-aided drug design of Keap1-Nrf2 inhibitors and the effect of physicochemical parameters on biomolecule interactions
Author: Kramar, S.
ISNI:       0000 0004 5351 8671
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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The rational design of novel chemotherapeutics is based upon knowledge of the intermolecular interactions between ligands and their targets, and the physical, topological and dynamic properties of those ligands within the biological environment. The pyrrolo(2,1-c)(1,4)benzodiazepine-5-ones (PBDs) are a family of sequence-selective, DNA minor groove-binding antitumour agents that inhibit transcriptional events and DNA replication. The effect of pH and salt concentrations on the conjugation rates of two PBDs with short DNA sequences were quantified by HPLC analysis. To further understand how the binding interactions of PBDs with DNA are affected by varying electrolyte conditions, computational techniques including conformational searching and molecular dynamics simulations were applied. The effect of the environment on the conformation of ligands and their target interactions was further evaluated and utilised in the design of Keap1-Nrf2 protein-protein interaction (PPI) inhibitors. Inhibition of this PPI increases the free concentration of Nrf2, a redox transcription factor which plays important roles in controlling xenobiotic and oxidative stress. Inhibitors could therefore act as cytoprotective agents in a range of diseases. A series of peptides with minor sequence modifications that interact with Keap1 were evaluated using computational approaches including: conformational searching (MacroModel), simulated annealing and molecular dynamics (Desmond). Binding poses of peptides in complex with Keap1 based on the structural information from the crystal structure of the Keap1-Nrf2 complex (PDB entry 1X2R) were predicted using several molecular docking programs (Hex, GLUE, Glide, GOLD). Finally, a series of reference crystal structures of a small molecule and peptides in complex with Keap1 were used as templates for the rational design of potential inhibitors of the Keap1-Nrf2 PPI. ‘Scaffold hopping’ (Spark) and free energy perturbation (FEP) (MCPRO) calculations were applied during the inhibitor design to provide possible replacements for key structural elements. This resulted in a virtual library of potential non-peptide inhibitors of the Keap1-Nrf2 PPI for future synthesis and evaluation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available