Crystallographic structure versus homology model: a case study of molecular dynamics simulation of human and...

Histone deacetylase (HDAC) 10 has been implicated in the pathology of various cancers and neurodegenerative disorders, making the discovery of novel inhibitors of the isoform an important endeavor. However, the unavailability of crystallographic structure of human HDAC10 (hHDAC10) hinders structure-based drug design effort. Previously, we reported the homology modeled structure of human HDAC10 built using the crystallographic structure of Danio rerio (zebrafish) HDAC10 (zHDAC10) (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) as a template. Here, in continuation with our study, both hHDAC10 and zHDAC10, and their respective complexes with trichostatin A (TSA), quisinostat, and the native ligand (in 5TD7), 7-[(3-aminopropyl)amino]-1,1,1-trifluoroheptane-2,2-diol (PDB ID; FKS) were submitted to 100 ns-long unrestrained molecular dynamics (MD) simulations. Comparative analyses of the MD trajectories revealed that zHDAC10 and its complexes displayed higher stability than hHDAC10 and its corresponding complexes over time. Nonetheless, docking of active and inactive set molecules revealed that more reliable conformations of hHDAC10 could be obtained at an extended time period. This study may shed more light on the reliability of hHDAC10 modeled structure for use in selective inhibitor design.Communicated by Ramaswamy H. Sarma.