Objectives: Screen focused PPI and fragment libraries under ATP-locking conditions; apply optical-interference counterscreens and ATP-site competition to confirm interface binding; integrate HTRF FRET probes; derive interface-anchored pharmacophores and iterate fragment follow-ups guided by WP2 hotspots and smFRET signatures; develop chemotypes with PPI-compatible profiles; optimize hit series using ChemoDOTS and structure-based growing to generate interface-selective hit-to-lead candidates.
Expected results: At least two small-molecule series with assay-confirmed interface engagement; a methodology paper on interface-directed triage and fragment-to-lead progression.
Secondments: GU: In-cellulo engagement and functional validation (M20–23; 4 months); LEI: AI-driven prioritisation and enrichment modelling (M31–33; 3 months).
Integration: Primary small-molecule discovery stream feeding WP4; tightly coupled to WP1 interference counterscreens and WP2 structural/mechanistic constraints.
Interdisciplinarity: Combines PPI-focused screening, biophysics-guided triage, in cellulo validation and AI-assisted optimisation.
