larger libraries have optimal chemo-diversity and unique scaffolds with drug-like
properties for HTS. Accordingly, this method can be implemented in epi-drug
discovery to identify the unique scaffolds that can be further optimized to design
high-affinity lead molecules with enhanced activity (Fig. 4).
Strategy 8. Structure-based drug discovery in epigenetics
Structure-based drug design (SBDD, also known as rational drug design) is an
essential tool in drug discovery and has delivered many successful drugs [100–
105]. In contrast to conventional ways of drug discovery (which are mostly hit and
trials), SBDD is more efficient since it incorporates the 3D structural information of
biological targets to understand their functional role in a disease [106]. SBDD
methods are now often applied much earlier in the drug discovery to save resources
and time during preclinical and early clinical stages.
SBDD begins with the selection of a potent biological target for a given therapeutic need. Once a target is selected, its structure must be determined to identify
potential ligand binding site using techniques such as X-ray crystallography,
cryo-EM (cryo-electron microscopy), and NMR (nuclear magnetic resonance
spectroscopy). The ligand binding site is ideally defined by a variety of hydrogen
bond donors and acceptors, hydrophobic residues, and molecular surface area. In
cases, where the structure of the target protein is not available, a homology model
can be deduced using computational tools such as SWISS-MODEL [107], Modeller
[108], Phyre2 [109]. Finally, a lead molecule is designed to interact with the target
Fig. 4 Barriers in drug discovery
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properties for HTS. Accordingly, this method can be implemented in epi-drug
discovery to identify the unique scaffolds that can be further optimized to design
high-affinity lead molecules with enhanced activity (Fig. 4).
Strategy 8. Structure-based drug discovery in epigenetics
Structure-based drug design (SBDD, also known as rational drug design) is an
essential tool in drug discovery and has delivered many successful drugs [100–
105]. In contrast to conventional ways of drug discovery (which are mostly hit and
trials), SBDD is more efficient since it incorporates the 3D structural information of
biological targets to understand their functional role in a disease [106]. SBDD
methods are now often applied much earlier in the drug discovery to save resources
and time during preclinical and early clinical stages.
SBDD begins with the selection of a potent biological target for a given therapeutic need. Once a target is selected, its structure must be determined to identify
potential ligand binding site using techniques such as X-ray crystallography,
cryo-EM (cryo-electron microscopy), and NMR (nuclear magnetic resonance
spectroscopy). The ligand binding site is ideally defined by a variety of hydrogen
bond donors and acceptors, hydrophobic residues, and molecular surface area. In
cases, where the structure of the target protein is not available, a homology model
can be deduced using computational tools such as SWISS-MODEL [107], Modeller
[108], Phyre2 [109]. Finally, a lead molecule is designed to interact with the target
Fig. 4 Barriers in drug discovery
Integrated Chemoinformatics Approaches …
261