Thesis

Advancing the use of simulation methods in structure-based drug discovery

Downloadable Content

Download PDF
Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2020
Thesis identifier
  • T17438
Person Identifier (Local)
  • 201671403
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • The role of simulation methods in industrial Structure-Based Drug Design (SBDD) is here investigated with focus on the bromodomain-containing protein 4 (BRD4). New tools were developed and applied, in conjunction with existing techniques, to study four problems in SBDD. Firstly, the ability to predict the water network at the bottom of the BRD4 protein was studied with 3D-RISM. The difficulties identified with the available tools led to the development of a new algorithm, GAsol. The results show that GAsol can accurately predict the most probable locations of the individual water molecules in the cavity of BRD4 protein. Secondly, since an incorrect interpretation of the ligand-binding mode in a crystal structure could compromise the overall SBDD process, Binding Pose MetaDynamics (BPMD) was investigated as a quantitative tool to assess the stability of protein-ligand complexes in solution. BPMD clearly separates ligands whose binding pose is supported (stable) and not (unstable) by the electron density. Thirdly, simulation methods were used to guide the design of a probe for the BRD4 protein with selectivity for the BD1 domain over BD2. The generated hypotheses were explored by means of Molecular Dynamics (MD) and MetaDynamics (MetaD) simulations. Insights on the role played by specific water molecules and residues enabled the design of several compounds which culminated with the identification of the desired probe. Finally, the interconversion between two binding modes seen in the X-ray crystal structures of a GSK-ligand in complex with the BRD4 protein is studied with MD, MetaD and a strategy of docking and BPMD. While MD was partially successful in reproducing the multiple ligand binding modes and MetaD with the funnel restraints was not, the docking and BPMD protocol showed promising results.
Advisor / supervisor
  • Wall, Ian (Ian J.)
  • Palmer, David
Resource Type
Note
  • The confidentiality statement on each page of this thesis DOES NOT apply.
  • Previously held under moratorium in Chemistry department (GSK) from 18th March 2020 until 15th August 2025.
DOI
Funder

Relations

Items

Thumbnail Title Date Uploaded Visibility Actions
file details PDF of Thesis T17438 2025-08-21 Public Download