Chemistry Reference
In-Depth Information
drug design (docking, scoring and molecular dynamics) and ligand-based drug
design (pharmacophore, QSAR and focused libraries).
It is possible to do good work using fragment docking combined with expanded
sampling. Fragment-specific scoring functions may be necessary however to
improve binding energy predictions. Fragments have less hydrogen bond donors
and acceptors, less rotable bonds, more translational and rotational freedom. Thus,
care should be taken to calculate entropic contributions [151]. The concept of
'ligandability' (where high values indicates that a protein is likely to bind
fragments with good affinity) can be used to estimate binding to targets by
docking fragments.
It is possible to evaluate each fragment of a decomposed compound
via
a pre-
docked database. Each fragment ranked according to specific interactions with the
receptor. New compounds can be formed replacing and reassembling the best
binding fragments to yield improved analogs. If a sufficient number of fragments
are used, fragment docking should give good results [150-229].
CONSENSUS DOCKING
There are a number of well-established and successful strategies in the literature
for discovering protein ligands. The strategies are twofold. First, the compounds
screened/docked into the active site of a protein structure model yields
conformation, location and orientation (pose). Subsequently, the pose is used to
calculate a predicted binding affinity of the compound with the protein. The
accuracy of the score is dependent on the accuracy of the predicted binding pose.
The virtual screening method has the limitation that significantly different poses
can yield similar docking scores (without possibility of distinguishing the correct
pose). The hit rates of virtual screening obtained from incorrect poses results in
incorrect affinity predictions.
Predicting affinity of a compound for a protein is challenging. In order to reduce
the error it is common to combine the results of several scoring algorithms into a
consensus-scoring scheme. Consequently, we have consensus scoring which is a
method whereas binding affinities of compounds for a particular target are
