2024 | Fady Baselious, Sebastian Hilscher, Dina Robaa, Cyril Barinka, Mike Schutkowski, and Wolfgang Sippl
This study presents a comparative structure-based virtual screening approach using an optimized AlphaFold model to identify selective HDAC11 inhibitors. HDAC11, a class IV histone deacetylase, lacks a known crystal structure and has low sequence identity with other HDAC isoforms, making conventional homology modeling unreliable. The optimized AlphaFold model was created by adding the catalytic zinc ion and minimizing the model in the presence of reported HDAC11 inhibitors. The virtual screening process involved a stepwise approach, including structure-based pharmacophore screening, ligand docking, pose filtering, and prioritization. The final hits were tested in vitro using an enzymatic assay, and the most promising compound showed an IC50 value of 3.5 μM for HDAC11 and selective inhibition over other HDAC subtypes at 10 μM concentration. Molecular dynamics simulations confirmed the binding hypothesis obtained from the docking study, further validating the optimized AlphaFold model for drug discovery. The study demonstrates the effectiveness of the optimized AlphaFold model in identifying novel and selective HDAC11 inhibitors, highlighting its potential in drug design for this challenging target.This study presents a comparative structure-based virtual screening approach using an optimized AlphaFold model to identify selective HDAC11 inhibitors. HDAC11, a class IV histone deacetylase, lacks a known crystal structure and has low sequence identity with other HDAC isoforms, making conventional homology modeling unreliable. The optimized AlphaFold model was created by adding the catalytic zinc ion and minimizing the model in the presence of reported HDAC11 inhibitors. The virtual screening process involved a stepwise approach, including structure-based pharmacophore screening, ligand docking, pose filtering, and prioritization. The final hits were tested in vitro using an enzymatic assay, and the most promising compound showed an IC50 value of 3.5 μM for HDAC11 and selective inhibition over other HDAC subtypes at 10 μM concentration. Molecular dynamics simulations confirmed the binding hypothesis obtained from the docking study, further validating the optimized AlphaFold model for drug discovery. The study demonstrates the effectiveness of the optimized AlphaFold model in identifying novel and selective HDAC11 inhibitors, highlighting its potential in drug design for this challenging target.