Abstract
Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.0.5 package. Various analyses of trajectories obtained from MD simulations have displayed the changes upon inhibitor binding. Thus utilization of the dynamically-responded protein structures in pharmacophore development has the added advantage of considering the conformational flexibility of protein. The MD trajectories were clustered based on single-linkage method and representative structures were taken to be used in the pharmacophore model development. Active site complimenting structure-based pharmacophore models were developed using Discovery Studio 2.5 program and validated using a dataset of known HDAC8 inhibitors. Virtual screening of chemical database coupled with drug-like filter has identified drug-like hit compounds that match the pharmacophore models. Molecular docking of these hits reduced the false positives and identified two potential compounds to be used in future HDAC8 inhibitor design.
Highlights
Histone deacetylase (HDAC) is a zinc-dependant enzyme involved in the deacetylation of terminal acetylated lysine residues of histone proteins [1,2,3]
Two most active Histone deacetylase 8 (HDAC8) inhibitors were selected from a set of inhibitory molecules with the experimental activity values determined using the same biological assay procedure collected from the literature
These two compounds were selected to be used in molecular dynamic (MD) simulation studies and the dynamic structures of HDAC8 complexed with these two diverse inhibitors were used in structure-based pharmacophore modeling
Summary
Histone deacetylase (HDAC) is a zinc-dependant enzyme involved in the deacetylation of terminal acetylated lysine residues of histone proteins [1,2,3]. Design and evaluation of linkerless hydroxamic acid derivatives reported that these new linkerless scaffolds have shown >100 fold selectivity for HDAC8 over other Class I and II HDACs. In addition, it is reported that the active site of HDAC8 is unconventionally malleable and can accommodate inhibitors of diverse structures with no conventional structural arrangement, which is “ZBM-linker-HCG” [19]. Though the differences in the crystal structures showcase interesting information that they can be used in designing new class of selective inhibitors, the conformational flexibility of the enzyme has become indispensable to be considered. MD simulations of these complexes were performed and the representative structures from the highly clustered conformations of MD simulation trajectory were selected to be used in the development of pharmacophore models These pharmacophore models, after validation, were used in virtual screening to identify new and potential hits for future drug design. We obtained two potential compounds which can be used in future HDAC8 inhibitor design
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