(lower molecular weight), which in a combination would work to a good molecule,
would have been screened out in regular HTS workflow; this method can show and
exploit the potential of different functional groups and core structures in harboring
key interactions with the active site pocket.
Pharmacophore modeling
Pharmacophore is the method to identify and understand the structural features of
the active site or ligand-binding site of receptor which is responsible for the biological activity. Recent years had witnessed the extensive use of pharmacophore
individually or in combination with various SBDD methods for better results [143–
146]. The structural aspects and the model are derived from the sets of ligand
molecule which are substrates or reported binders toward the target protein. This
model which is derived projects the requirements which are important for ligands to
bind to receptor for their recognition, leading to biological response. The pharmacophore model can be established as a ligand-based or in a structure-based
manner.
Ligand-based pharmacophore modeling
Common chemical features are extracted from the three-dimensional structures of a
set of known ligands. During the pharmacophore generation, the conformational
space for each ligand in the training set is created which represents the conformational flexibility of ligands. Some of the commercially available software
packages for pharmacophore modeling are HipHop, Hypogen (http://accelrys.com/
services/training/life-science/pharmacophore-modeling.html), DISCO, GASP
(http://pharmacophore.org/), Phase (https://www.schrodinger.com/), molecular
operating environment (MOE, https://www.chemcomp.com), etc. There are also
several academic programs available. In these programs, algorithms are used for
handling the flexibility of ligands [147, 148] and for the alignment of molecules.
Quantitative structure–activity relationship (QSAR)
For the correlation of biological activity with the molecular properties (descriptors)
calculated from the two-dimensional or three-dimensional structures of ligands
[149], QSAR is used. For forming a linear equation of this type, a set of ligands
with the known biological activities called the training set is essential. Unknown
activity of novel compounds can then be predicted using the relationship: v = f(p),
where v is the biological activity and p is a set of descriptor properties. Most of the
software packages listed for pharmacophore modeling are having QSAR modules.
Most widely used methods are kNN, PLS, MLR, etc., and these functionalities are
available with different software packages such as VLife sciences, Schrodinger, and
MOE.
Peptide-based drugs
Drugs which are available can be categorized into smaller molecules which are
usually <500 Da, and others are larger molecules with molecular weight >5000 Da.
The lower molecular weight drugs can be orally administered, and larger ones are
delivered through injections.
Structure-Based Drug Design…
287
would have been screened out in regular HTS workflow; this method can show and
exploit the potential of different functional groups and core structures in harboring
key interactions with the active site pocket.
Pharmacophore modeling
Pharmacophore is the method to identify and understand the structural features of
the active site or ligand-binding site of receptor which is responsible for the biological activity. Recent years had witnessed the extensive use of pharmacophore
individually or in combination with various SBDD methods for better results [143–
146]. The structural aspects and the model are derived from the sets of ligand
molecule which are substrates or reported binders toward the target protein. This
model which is derived projects the requirements which are important for ligands to
bind to receptor for their recognition, leading to biological response. The pharmacophore model can be established as a ligand-based or in a structure-based
manner.
Ligand-based pharmacophore modeling
Common chemical features are extracted from the three-dimensional structures of a
set of known ligands. During the pharmacophore generation, the conformational
space for each ligand in the training set is created which represents the conformational flexibility of ligands. Some of the commercially available software
packages for pharmacophore modeling are HipHop, Hypogen (http://accelrys.com/
services/training/life-science/pharmacophore-modeling.html), DISCO, GASP
(http://pharmacophore.org/), Phase (https://www.schrodinger.com/), molecular
operating environment (MOE, https://www.chemcomp.com), etc. There are also
several academic programs available. In these programs, algorithms are used for
handling the flexibility of ligands [147, 148] and for the alignment of molecules.
Quantitative structure–activity relationship (QSAR)
For the correlation of biological activity with the molecular properties (descriptors)
calculated from the two-dimensional or three-dimensional structures of ligands
[149], QSAR is used. For forming a linear equation of this type, a set of ligands
with the known biological activities called the training set is essential. Unknown
activity of novel compounds can then be predicted using the relationship: v = f(p),
where v is the biological activity and p is a set of descriptor properties. Most of the
software packages listed for pharmacophore modeling are having QSAR modules.
Most widely used methods are kNN, PLS, MLR, etc., and these functionalities are
available with different software packages such as VLife sciences, Schrodinger, and
MOE.
Peptide-based drugs
Drugs which are available can be categorized into smaller molecules which are
usually <500 Da, and others are larger molecules with molecular weight >5000 Da.
The lower molecular weight drugs can be orally administered, and larger ones are
delivered through injections.
Structure-Based Drug Design…
287