Comparative Structure Based Virtual Screening Utilizing Optimized AlphaFold Model Identifies Selective HDAC11 Inhibitor

• DOI: 10.26434/chemrxiv-2023-cljlr
• Publication Date: 2023-12-05T05:12:02Z
• Authors: Fady Baselious; Sebastian Hilscher; Dina Robaa; Cyril Barinka; Mike Schutkowski; Wolfgang Sippl
• Keywords: HDAC11; Docking (animal)

HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of shares low sequence identity other HDAC isoforms which makes the conventional homology modeling less reliable. AlphaFold neural network machine learning approach that can predict 3D proteins high accuracy even in absence similar structures. However fact models are predicted small molecules and ions/cofactors complicate their utilization for drug design. Previously we optimized an model by adding zinc ion minimization presence inhibitors. In current study implement comparative structure-based virtual screening utilizing previously to identify novel selective stepwise was successful identifying hit subsequently tested using vitro enzymatic assay. compound showed IC50 value 3.5 µM could selectively inhibit over subtypes at 10 concentration. addition carried out molecular dynamics simulations further confirm binding hypothesis obtained docking study. These results reinforce presented optimization applicability search inhibitors discovery.