• Identification of unique subtype-specific interaction features in Class II zinc-dependent HDAC subtype binding pockets: A computational study

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    • Keywords


      Anticancer drug design; docking; histone deacetylase (HDAC); molecular dynamics simulations; pharmacophore; subtype specificity

    • Abstract


      Zinc-dependent HDAC subtypes (ZnHDACs) exhibit differential expression in various cancer types andsignificantly contribute to oncogenic cell transformation, and hence are interesting anticancer drug targets. Theapproved pan HDAC inhibitors (PHIs) lack subtype specificity and inhibit all ZnHDACs, causing severe sideeffects.Considering the distinct tissue distribution and roles of individual ZnHDACs in specific cancer types, itis crucial to rationally design subtype-specific inhibitors (SSIs) for enhanced efficacy and reduced side-effects.There are numerous approaches already conducted for designing SSIs, especially Class I ZnHDACs, whereasClass II and III ZnHDACs are relatively unexplored and equally important in disease pathogenesis. This studyattempts to decipher the specificity rendering interaction features of six different ZnHDACs by robust analysesof reported experimental data employing sophisticated computational methods like homology modelling,docking, pharmacophore analysis, and molecular dynamic (MD) simulations. Experimentally validated SSIs(activity less than 1000 nM) of different ZnHDACs and 8 approved PHIs were docked to 40 MD generated conformationsof each ZnHDACs followed by MM-GBSA binding energy estimations. Sequences, structures,physicochemical properties, and interaction patterns of the binding sites obtained from docking wereexhaustively compared to identify unique subtype-specific interaction features for each Class II ZnHDACs. Tofurther validate the stabilities of these features, 20 ns MD simulations were performed on 12 complexes (eachClass II ZnHDACs bound to one SSI and one PHI) in explicit water models. Distinct pharmacophoric patternswere observed in the binding pockets of each subtype despite high sequence similarities. Presence of amides,ketone, hydroxyl, carboxyl groups, and moieties occupying additional sub-pockets and interacting with Zn 2+,etc., in the SSIs affect the orientations of the binding site residues (BSRs) owing to subtype-specific protein–ligand interactions. Stable and unique residue interactions specific for a HDAC subtype are, e.g. E329 forHDAC4, S904 for HDAC5, W496 S563 I569 for HDAC6, M793 for HDAC9, and E302 for HDAC10. Suchunique interaction features and pharmacophoric patterns can be utilized for subtype-specific ZnHDAC inhibitordesign.

    • Author Affiliations



      1. Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Industrial Area Phase II, Basni, Jodhpur, Rajasthan 342 005, India
      2. Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India
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