Histone pharmacophore

Crystal structures of a histone deacetylase-like protein (HDLP) and HDAC8 have confirmed a general pharmacophore model for HDAC inhibitors, comprising a cap joined by a hydrophobic linker to a zinc-binding group (ZBG). This model is exemplified by SAHA and the natural product HDACi Trichostatin A (TSA) 2. 

Vadivelan, S., Sinha, B.N., Rambabu, G., Boppana, K. and Jagarlapudi, S. (2008) Pharmacophore modeling and virtual screening studies to design some potential histone deacetylase inhibitors as new leads. Journal of Molecular Graphics ei Modelling, 26, 935—946. 

Tervo et al. [155] described a successful virtual screening experiment for the class III histone deacylase sirtuin type 2 (SIRT2). Using two databases of commercially available compounds plus a receptor-based pharmacophore query, 4 out of 11 tested molecules showed weak to moderate inhibitory activity. The two most active inhibitors vdth IC50 values of 51 and 91 pM had new scaffolds (Figure 12.14b). 

Figure 12.14 Ligand-based virtual screening examples for miscellaneous targets, (a) a4pi (VLA-4) antagonist from pharmacophore searching, IC50 1 nM. (b) Class III histone...

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