Locating a ligand-binding site is an important first step in structure-guided drug discovery, but current methods typically assess the pocket as a whole, doing little to suggest which regions and interactions are the most important for binding. This thesis introduces Fragment Hotspot Maps, a grid-based method that samples atomic propensities derived from interactions in the Cambridge Structural Database (CSD) with simple molecular probes. These maps specifically highlight fragment-binding sites and their corresponding pharmacophores, offering more precision over other binding site prediction methods.

The method is validated by scoring the positions of 21 fragment and lead pairs. Fragment atoms are found in the highest scoring parts of the map corresponding to their atom type, with a median percentage rank of 98%. This is reduced to 72% for lead atoms, showing that the method can differentiate between the hotspots, and the warm spots later used during fragment elaboration.

For ligand-bound structures, they provide an intuitive visual guide within the binding site, directing medicinal chemists where to grow the molecule and alerting them to suboptimal interactions within the original hit. These calculations are easily accessible through a simple to use web application, which only requires an input PDB structure or code.

High scoring specific interactions predicted by the Fragment Hotspot Maps can be used to guide existing computer aided drug discovery methods. The Hotspots Python API has been created to allow these work flows to be executed programmatically through a single Python script. Two of the functions use scores from the Fragment Hotspot Maps to guide virtual screening methods, docking and field-based ligand screening. Docking virtual screening performance is improved by using a constraint selected from the highest scoring polar interaction. The field-based ligand screener uses modified versions of the Fragment Hotspot Maps directly to predict and score the binding pose. This workflow gave comparable results to docking, and for one target, Glucocorticoid receptor (GCR), showed much better results, highlighting its potential as an orthogonal approach.

Fragment Hotspot Maps can be used at multiple stages of the drug discovery process, and research into these applications is ongoing. Their utility in the following areas are currently being explored: to assess ligandability for both individual structures and across proteomes, to aid in library design, to assess pockets throughout a molecular dynamics trajectory, to prioritise crystallographic fragment hits and to guide hit-to-lead development.