Chemistry Reference
In-Depth Information
the overall binding energy. Probe docking can select features at positions where
probes have high interaction energies. If multiple ligands are available and
binding mode hypothesis generated, features, which correlate with conserved
protein-ligand interactions can be identified.
Selection of important binding site amino acid residues can be done through
evaluation of sequence variations. Known active compounds can be used to select
specific combinations of pharmacophore features and include shape restraints in
the SBP model. Shape and volume restraints are important concepts for virtual
screening and lead optimizations. SBPs can be used to improve molecular
understanding of ligand-protein interactions, virtual screening, ligand binding
mode prediction and binding site similarity detection. Ligand- and protein
structure-based methods are complementary approaches for identifying different
ligand chemotypes suggesting models that are a combination of LBP and SBPs.
X-ray crystallizations and NMR spectroscopy are well suited for combination
with SBPs.
SBPs can be detected by a number of methods. These include grid generation,
molecular dynamics, protein-ligand complexes, overlay based clustering,
homology models, chemoprints and geometry-based models. They can also help
understand the interaction of ligands with proteins, affinity/selectivity prediction,
hit optimization, structure-activity relationships, binding pocket exploration,
targeting excluded residues, correct ligand binding prediction and even compare
ligand-binding sites.
Geometric methods to derive SBPs are often the least restrictive. This protocol
together with the probe-based method are the approaches applied in the absence of
known ligands. Reduction of the high number of features is a challenge in SBP in
order to obtain characteristic of biological activity interest. Energy based methods
depend on the accuracy of input/binding modes. Statistical protocols can work
with low quality structures. The pharmacophore concept is relatively simple
yielding an attractive tool for research applications [255-269]. Discovery Studio
(Accelrys software) is one of the softwares for pharmacophe modeling. In the
sections on docking and virtual screening programs we describe fitty one
programs that use diversified protocols including pharmacophores.
