Use of fragment-based drug discovery to identify novel drug molecules for challenging biological targets, including protein-protein interactions

Previously held under moratorium in Chemistry department (GSK) from 25/05/2016 until 18/06/2021.The confidentiality statement on each page of this thesis DOES NOT applyThis research programme describes two of the first fragment-based drug discovery (FBDD) programmes pursued within our laboratories. In recent years, increased emphasis has been placed on careful control of physicochemical properties in the search for safe and efficacious medicines. FBDD has been proposed as a complementary technique to high throughput screening (HTS) resulting in the identification of small, polar, highly efficient fragments that bind to the target of interest. The targets pursued within this programme of work each represent a distinct biological challenge: a protein-protein interaction (HIV Integrase-LEDGF) with large surface contacts to disrupt, and a hydrolase enzyme (CD38) with a large open active site. The challenge of optimising the CD38 fragments was heightened due to the inability to obtain X-ray crystal structures of the series of interest. The rigorous FBDD screening, design, and optimisation process is described, resulting in identification of lead molecules with reduced liabilities, and improved physicochemical properties compared to HTS-derived templates. These molecules provide good tools to aid in mode of action studies and future drug development. Insight from these studies has resulted in recommendations for the most effective approach towards target tractability assessment, screening, and fragment optimisation strategies. Incorporation of the outputs from this programme will have an impact on the ethos and practice of FBDD methodology and how this strategy is implemented into future ‘hit-to-lead’ efforts. It is anticipated that this will, in turn, reduce associated timelines and, therefore, make a valuable addition to such ‘hit-to-lead’ programmes.This research programme describes two of the first fragment-based drug discovery (FBDD) programmes pursued within our laboratories. In recent years, increased emphasis has been placed on careful control of physicochemical properties in the search for safe and efficacious medicines. FBDD has been proposed as a complementary technique to high throughput screening (HTS) resulting in the identification of small, polar, highly efficient fragments that bind to the target of interest. The targets pursued within this programme of work each represent a distinct biological challenge: a protein-protein interaction (HIV Integrase-LEDGF) with large surface contacts to disrupt, and a hydrolase enzyme (CD38) with a large open active site. The challenge of optimising the CD38 fragments was heightened due to the inability to obtain X-ray crystal structures of the series of interest. The rigorous FBDD screening, design, and optimisation process is described, resulting in identification of lead molecules with reduced liabilities, and improved physicochemical properties compared to HTS-derived templates. These molecules provide good tools to aid in mode of action studies and future drug development. Insight from these studies has resulted in recommendations for the most effective approach towards target tractability assessment, screening, and fragment optimisation strategies. Incorporation of the outputs from this programme will have an impact on the ethos and practice of FBDD methodology and how this strategy is implemented into future ‘hit-to-lead’ efforts. It is anticipated that this will, in turn, reduce associated timelines and, therefore, make a valuable addition to such ‘hit-to-lead’ programmes