Protein domain movement involved in binding of belinostat and HPOB as inhibitors of histone deacetylase 6 (HDAC6): a hybrid automated-interactive docking study

Iakovou, Georgios, Palmer, Leoni, Ganesan, A., Kitao, Akio, Laycock, Stephen D. and Hayward, Steven (2025) Protein domain movement involved in binding of belinostat and HPOB as inhibitors of histone deacetylase 6 (HDAC6): a hybrid automated-interactive docking study. Journal of Computer-Aided Molecular Design, 39. ISSN 0920-654X

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Abstract

DockIT is a tool for interactive molecular docking that can model both the local and global conformational response of the receptor to the docking of a ligand based on information from a molecular dynamics simulation. Using DockIT we have investigated the binding process of two histone deacetylase (HDAC) inhibitors to HDAC6: the nonselective approved drug belinostat and the preclinical HPOB. To model HDAC6’s conformational response to the binding of the inhibitors we performed a 200-nanosecond explicit-solvent molecular dynamics simulation on HDAC6. Unexpectedly the simulation revealed a domain movement that affects the size and shape of the binding pocket. Using automated docking and a rigid model for the inhibitors, the domain movement continuously adapts the pocket to the presence of the inhibitor. For both inhibitors, an intermediate binding site was found where it was partially inserted, with a hydrogen bond formed between the inhibitor’s hydroxamic acid and the Tyr745 side chain. Pushing the inhibitor deeper into the pocket over an energy barrier and re-engaging automated docking, a final binding pose resulted with a root-mean square deviation with its respective crystallographic pose of 1.0 Å for belinostat and 1.4 Å for HPOB. We believe our results mimic substrate recognition by the enzyme, with an initial partial binding of the acetyllysine residue with Tyr745. During binding a relay of hydrogen bonds occurs coordinating the orientation of the cap and the hydroxamic acid inside the pocket. The interaction between the cap and the surface of HDAC6 explains the reason for the hydroxamic acid warhead in HPOB binding in a flipped orientation compared to belinostat.

Item Type:	Article
Additional Information:	Data availability statement: DockIT is free for non-commercial use and can be downloaded from https://expresslicensing.uea.ac.uk/product/dockit. Structure files, topology files, eigenvalue and eigenvector files to run DockIT with HDAC6 as the receptor and belinostat and HPOB as the ligand are available from this link: 10.5281/zenodo.15528370. Also available are ghost ligand structure files and DockIT workspace files. The results described in this article can be reproduced by loading these workspace files into DockIT and starting automated docking by pressing the “Auto” button.
Faculty \ School:	Faculty of Science > School of Computing Sciences Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
UEA Research Groups:	Faculty of Science > Research Groups > Computational Biology Faculty of Science > Research Groups > Health Technologies Faculty of Science > Research Groups > Visual Computing and Signal Processing
Depositing User:	LivePure Connector
Date Deposited:	16 Jul 2025 10:34
Last Modified:	18 Jul 2025 00:12
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99946
DOI:	10.1007/s10822-025-00636-x

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