Chemistry Reference
In-Depth Information
performance of search methods. VS techniques require further improvements to
meet the challenges [418-456]. There are numerous docking and virtual screening
programs. Some of these protocols will be reviewed in subsequent sections of this
chapter [492-546].
WORKFLOW PIPELINES
We refer herewith to more efficient virtual screening protocols. These are cyclic
process with each cycle leading to more accurate data. This often involves
applying hierarchy of filters of increasing selectivity in order to reduce rationally
large virtual libraries to smaller sets of candidate molecules for experimental
evaluation. The procedure uses fast filtering funnels first and subsequently more
computationally expensive tools to distinguish remaining candidates [457-463].
Molecules can be first selected with good ADME-Tox properties and drug-like
features in order to improve pharmacokinetics and potency. Subsequently, 2D or
3D similarity filters can be used for further screening followed by pharmcophore
modeling to obtain desired structural chemical features. Further filtering involves
docking with molecular dynamics in order to predict binding modes and optimize
substituents. Lead candidates can then progress to stages of synthesis and testing
and the results re-cycled through 3d QSAR and ADME-Tox prediction models.
Multiple levels of varying sensitive filters (ADME-Tox and scoring) can be used
to scan very large libraries (hierarchical screening
via
combination of LBVS and
LBVS methods). More advanced workflows management systems can be used to
make the tasks accessible providing flexible frameworks to build complex
workflows and analysis pipelines [457-463].
DIFFERENT TYPES OF LIGANDS/TARGETS/INTERACTIONS
For ligand-protein interactions, most docking protocols have been developed for
traditional small organic molecules. There are however ligands/targets/interactions that
merit special attention. We will comment briefly on some of these cases [789-811].
Hydrogen bonds interactions are mainly electrostatic soft interactions. They are
dependent on the pair of atom groups that forms the acceptor donor subunits.
