Chemistry Reference
In-Depth Information
putative ligand. The traditional 'lock and key' paradigm can provide satisfactory
results for biologically active rigid sites or conformation-selective inhibitors.
SBP's can be used for target fishing (find new targets for specific ligands). They
can yield insight into ligand-protein interactions, ligand-protein interactions and
enable ligand profiling (structural chemogenomics studies aimed at identification
of new ligands for specific proteins). They can allow identification of novel
scaffolds, elucidation of protein-ligand chemotypes/binding modes, provide tools
for structure-based ligand optimization and increase comprehension of binding
sites. They can also find ligands for orphan receptors and allow cross-
pharmacology applications in order to suggest new targets for existing drugs.
We can divide the preparation of SBPs into four major steps,
i.e.
protein structure
preparation, binding site detection; pharmacophore feature definition and
selection. At the protein, backbone, polar hydrogen atoms, side chains potential
conformation, and protonation states variations are expected to be larger making
the selection of pharmacophore features more complex than in ligand-based
pharmacophores.
The pre-requisite for SBP method is the availability of a 3d protein structure.
Subsequently, protein structure preparation is required (including non-protein
groups such as water molecules, determination of protonation states, position of
hydrogen atoms and consideration of protein conformations). The biologically
active ligand conformation is typically used to align multiple active molecules and
deduce a pharmacophore. Subsequently it is necessary to define the location of the
ligand-binding site using appropriate algorithms. In a subsequent stage,
pharmacophore features can be obtained from co-crystallized ligands or ligand
binding sites.
Favorable interactions can be characterized by geometric entities, spheres, vectors
and planes and common interaction types include H-bond acceptors, H-bond
donors, ionizable groups, aromatic rings and liphophilic regions. For compound
library enrichment and binding mode hypothesis, it is necessary to select features,
which correlate with biological activity. Protein-ligand interaction energies can
estimate and prioritize interactions and discard those with small contributions to
