Histone deacetylase (HDAC) 8 has been implicated as a potential therapeutic target in a variety of cancers, neurodegenerative disorders, metabolic dysregulation, and autoimmune and inflammatory diseases. Several nonselective HDAC inhibitors, including SAHA, TSA, M344, PTSB-hydroxamate, CRA19156, aroyl pyrrole hydroxy amide (APHA), Trapoxin A, and largazole thiol, have been co-crystallized with HDAC8. Molecular dynamics (MD) studies examining the stability of these inhibitors in the active site of HDAC8 may provide a better sampling of the binding poses over time. Here, using 11 X-ray crystal structures of human HDAC8 (complexes) structure-based pharmacophore models were built and clustered based on distance which is a function of the number of common pharmacophore features and the root-mean-squared displacement between the matching features. Based on this information, one complex from each pharmacophore cluster (total of 7 pharmacophore clusters) was selected for further studies. A total of 7 complexes (1T64, 1W22, 3RQD, 3SFF, 3F0R, 5VI6, and 5FCW) were processed by insertion of missing atoms in incomplete residues, modelling missing loop regions based on primary sequence of the respective proteins, deleting alternate conformations, and protonating titratable residues using predicted pKa values. These complexes were then submitted to 200 ns-MD simulations.<br/>

Intermolecular interactions in human HDAC8 crystal structures and the stability of binding modes of co-crystallized inhibitors

2019 Fall National Meeting

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