the hit rate in VS [13, 14]. Satisfactory correlations have been obtained between
calculated binding affinities and experimental data, especially for ligand series with
high structural similarity [15]. Although previous applications of MM-PBSA and
MM-GBSA proved to be very useful and efficient in many macromolecular studies,
there remains still room for improvement in many aspects of existing methods,
including estimation of the solute entropy solvation free energy of polar compounds,
sampling of the conformational space of the protein-ligand interaction as well as
developing adequate parameters for describing the molecular structures. The above
described methods provide a set of computational tools for structure-based design of
epigenetic inhibitors.
3 Histone Deacetylases
The family of human histone deacetylases (HDACs) includes 18 isoforms and is
classified into two structurally distinct groups and five classes. The first group
is called zinc-dependent HDACs. It consists of 11 isoforms subdivided into four
classes: class I (HDAC1–HDAC3, HDAC8), class IIa (HDAC4–HDAC5, HDAC7,
HDAC9), class IIb (HDAC6 and HDAC10), and class IV (HDAC11). The second
group of HDACs is usually referred to as sirtuins. It comprises seven isoforms,
which all belong to class III [16]. Structural features of different HDAC groups,
classes, and isoforms are often addressed in the structure-based design of HDAC
inhibitors. Computational methods allow to visualize those features and to predict
protein-ligand interactions in a qualitative and quantitative manner as illustrated
further.
3.1 Zinc-Dependent HDACs
Zinc-dependent HDACs share a conserved deacetylase core domain [17]. To date,
more than 100 structures of these domains have been solved [18–26]. Their architecture is similar: an α/β fold formed by an ensemble of conserved α-helices,
β-sheets, and binding pocket loops as well as less conserved distant loops. The
residues of the binding pocket form an approximately 12 Å long substrate binding
tunnel with the catalytically important zinc ion at the bottom [27]. This tunnel and
adjacent cavities are usually targeted by inhibitors bearing a warhead containing a
zinc-binding group (examples are shown in Fig. 1).
The most common zinc-binding group is hydroxamic acid. Interestingly, it is able
to interact with the zinc ion either in a bidentate or a monodentate fashion, as seen,
for example, in the crystal structures of zebrafish HDAC6 with Panobinostat (1)
(PDB ID: 5EF8) and Nexturastat A (2) (PDB ID: 5G0I), correspondingly (Fig. 2). In
both cases, the hydroxamic acid group makes a number of hydrogen bonds to the
nearby amino acid residues, the hydrophobic spacer is stabilized by van der Waals
Structure-Based Design of Epigenetic Inhibitors
459
calculated binding affinities and experimental data, especially for ligand series with
high structural similarity [15]. Although previous applications of MM-PBSA and
MM-GBSA proved to be very useful and efficient in many macromolecular studies,
there remains still room for improvement in many aspects of existing methods,
including estimation of the solute entropy solvation free energy of polar compounds,
sampling of the conformational space of the protein-ligand interaction as well as
developing adequate parameters for describing the molecular structures. The above
described methods provide a set of computational tools for structure-based design of
epigenetic inhibitors.
3 Histone Deacetylases
The family of human histone deacetylases (HDACs) includes 18 isoforms and is
classified into two structurally distinct groups and five classes. The first group
is called zinc-dependent HDACs. It consists of 11 isoforms subdivided into four
classes: class I (HDAC1–HDAC3, HDAC8), class IIa (HDAC4–HDAC5, HDAC7,
HDAC9), class IIb (HDAC6 and HDAC10), and class IV (HDAC11). The second
group of HDACs is usually referred to as sirtuins. It comprises seven isoforms,
which all belong to class III [16]. Structural features of different HDAC groups,
classes, and isoforms are often addressed in the structure-based design of HDAC
inhibitors. Computational methods allow to visualize those features and to predict
protein-ligand interactions in a qualitative and quantitative manner as illustrated
further.
3.1 Zinc-Dependent HDACs
Zinc-dependent HDACs share a conserved deacetylase core domain [17]. To date,
more than 100 structures of these domains have been solved [18–26]. Their architecture is similar: an α/β fold formed by an ensemble of conserved α-helices,
β-sheets, and binding pocket loops as well as less conserved distant loops. The
residues of the binding pocket form an approximately 12 Å long substrate binding
tunnel with the catalytically important zinc ion at the bottom [27]. This tunnel and
adjacent cavities are usually targeted by inhibitors bearing a warhead containing a
zinc-binding group (examples are shown in Fig. 1).
The most common zinc-binding group is hydroxamic acid. Interestingly, it is able
to interact with the zinc ion either in a bidentate or a monodentate fashion, as seen,
for example, in the crystal structures of zebrafish HDAC6 with Panobinostat (1)
(PDB ID: 5EF8) and Nexturastat A (2) (PDB ID: 5G0I), correspondingly (Fig. 2). In
both cases, the hydroxamic acid group makes a number of hydrogen bonds to the
nearby amino acid residues, the hydrophobic spacer is stabilized by van der Waals
Structure-Based Design of Epigenetic Inhibitors
459