X-ray crystal structures of many epigenetic proteins, the SBDD approaches are not
competent in all circumstances. For example, the thermodynamics of ligand-receptor
association cannot be predicted precisely because the current methodologies do not
take into account the factors such as receptor flexibility, solvation, entropy, and
dynamic inclusion of water molecules [119, 120]. Additionally, some tricky epigenetic
targets such as HATs and other complexes lack potent chemical probes and are
unexplored [121]. Nevertheless, epigenetic drug discovery is evolving and it is necessary to have access to experimental data related to bioassays and 3D structures of
epigenetic enzymes. To support SBDD for epigenetic targets, EpiDBase [46] provides
information regarding available structures of epigenetic proteins with the
cross-reference to Protein Data Bank, resolution of crystal structures, the method of
obtaining crystal structure, and the information about ligand present in crystal structure, if any. EpiDBase can assist in homology modeling, docking, virtual screening
and can prove to be resourceful to accelerate structure-based drug discovery.
5 Conclusion and Future Perspectives
Transforming lead molecules into successful drugs is still a challenging task, in
spite of tremendous advances in pharmacology and medicinal chemistry [122]. In
fact, 99% of drug discovery projects fail and most leads are unable to make it
through the later stages of drug development (clinical trials). The advancement in
the knowledge of epigenetic changes associated with specific disease has encouraged the research efforts in the field of epigenetic drug discovery.
Box 1. Questions to ask before obtaining a chemical library
Questions?
Why ask?
Do the scaffolds overlap with the
biological space of epigenetic target
binding site?
The selection of scaffolds for a particular
target limits the chemical space and
provides the key building blocks while
designing the drugs
Do the scaffolds have synthetic
accessibility?
The synthesis of various derivatives can
be achieved for scaffolds, which
demonstrate synthetic tractability. This
will probably lower the cost of synthesis
and save time
Do the compounds exhibit favorable
physicochemical properties?
All chemical compounds are not drugs.
Drug-likeness of a compound depends on
various physical and chemical properties.
Compounds with favorable
physicochemical properties are more
promising at later stages of drug
development
(continued)
Integrated Chemoinformatics Approaches …
263
competent in all circumstances. For example, the thermodynamics of ligand-receptor
association cannot be predicted precisely because the current methodologies do not
take into account the factors such as receptor flexibility, solvation, entropy, and
dynamic inclusion of water molecules [119, 120]. Additionally, some tricky epigenetic
targets such as HATs and other complexes lack potent chemical probes and are
unexplored [121]. Nevertheless, epigenetic drug discovery is evolving and it is necessary to have access to experimental data related to bioassays and 3D structures of
epigenetic enzymes. To support SBDD for epigenetic targets, EpiDBase [46] provides
information regarding available structures of epigenetic proteins with the
cross-reference to Protein Data Bank, resolution of crystal structures, the method of
obtaining crystal structure, and the information about ligand present in crystal structure, if any. EpiDBase can assist in homology modeling, docking, virtual screening
and can prove to be resourceful to accelerate structure-based drug discovery.
5 Conclusion and Future Perspectives
Transforming lead molecules into successful drugs is still a challenging task, in
spite of tremendous advances in pharmacology and medicinal chemistry [122]. In
fact, 99% of drug discovery projects fail and most leads are unable to make it
through the later stages of drug development (clinical trials). The advancement in
the knowledge of epigenetic changes associated with specific disease has encouraged the research efforts in the field of epigenetic drug discovery.
Box 1. Questions to ask before obtaining a chemical library
Questions?
Why ask?
Do the scaffolds overlap with the
biological space of epigenetic target
binding site?
The selection of scaffolds for a particular
target limits the chemical space and
provides the key building blocks while
designing the drugs
Do the scaffolds have synthetic
accessibility?
The synthesis of various derivatives can
be achieved for scaffolds, which
demonstrate synthetic tractability. This
will probably lower the cost of synthesis
and save time
Do the compounds exhibit favorable
physicochemical properties?
All chemical compounds are not drugs.
Drug-likeness of a compound depends on
various physical and chemical properties.
Compounds with favorable
physicochemical properties are more
promising at later stages of drug
development
(continued)
Integrated Chemoinformatics Approaches …
263