This project aims to discover small-molecule modulators of the THIK-1 (K2P13.1) potassium channel using an integrated, structure-based discovery workflow. The K2P channel family are responsible for a wide variety of physiological roles, from pain regulation to mood. Starting from the lipid-bound cryo-EM structure at the modulator site, fragment-based virtual screening with BioSolveIT’s ChemSpaceDocking will sample chemically diverse, small molecules in the channel's binding pockets. Top-ranked ligands will be re-docked and rescored with mmGBSA, and candidates filtered by in silico ADMET properties to prioritise compounds with favourable profiles. Identified ligands will be tested by collaborators using electrophysiology and targeted mutagenesis to assess effects on THIK-1 function and validate binding hypotheses. Active hits will then be modified with infiniSee to explore local chemical space and design focused analogues for iterative optimisation of potency and selectivity.
Nathaniel intends to achieve the following milestones:
- Completion of chemical space docking and identifying of lead compounds
- Electrophysiology screening and targetted mutagenesis of identified candidates
- Hit expansion and optimisation of experimentally validated ligands