During the project so far we have performed fragment-based virtual screening of THIK-1 at the modulator site using the crystal structure (RCSB:9BYI) with ChemSpaceDocking and the Enamine REAL chemical space. Fragment selection was carried out over three steps, growing the synthon fragments each time. Synthons were selected for each step based on size, pose, and ligand efficiency. After three steps, the top 100,000 compounds were chosen and redocked using Glide SP, where π-π, H-bond interactions alongside docking scores were identified, with the top 10,000 poses retained. The top 20 compounds were further redocked using MM-GBSA to provide dG scores and better pocket residue conformers. The next steps will be a two-pronged approach of experimental validation and in silico ligand modification. MD simulations via Schrodinger Desmond can ascertain ligand stability to determine the best potential experimental candidates. InfiniSee scaffold hopping will be performed on MM-GBSA compounds.
After 3 months, Nathaniel has achieved the following milestones:
- Successful fragment-based virtual screening of Enamine REAL space, identifying 100,000 compounds, then docked using Glide SP. Out of 10,000 poses returned, best scoring compound was -11.403 kJ/mol, excellent for K2P modulator pocket, with the lowest at -8.592 kJ/mol. Average docking score was -8.979 kJ/mol. MM-GBSA returned top scoring compound of dG -101.52, with an average dG of -80.12.
- Best compounds have been identified and are subject to further screening and ADME-T scoring before purchase & experimental validation.
- Identified ligands will be used for InfiniSee scaffold hopping, then for each compound Glide SP docking performed to identify top compounds for further analysis.