induced fit or conformational selection case [14]. Existence of possibly alternate
interaction features in binding site could provide complementarity for even structurally very similar ligands but provide different poses; several such cases have
been reviewed by Teague et al. [147]. Another case could be enthalpy–entropy
compensation due to receptor–ligand flexibility for different poses of ligand [147].
Although docking and scoring lack capability to account entropy, considering
receptor–ligand flexibility in docking can be a poor proxy for entropy to certain
extents.
3.4 Flexibility of Ligand Provides Complementarity
Generally, small molecules can adopt a number of conformations within few kcal/
mol energy gap from the global minimum conformation. Thus, a number of conformations of ligands are generated and docked into the receptor to seek optimal
complementarity between receptor-binding site and the ligand conformation to yield
most probable pose. Therefore, several conformation generation schemes which can
be broadly put in two groups, (a) systematic search and (b) random search, have been
suggested and are routinely employed in docking studies [148]. Systematic search
tries to generate all the conformation corresponding to the rotational states for the
rotatable bonds of the molecule, but exponential increase of the number of conformations of the molecule with number of rotatable bonds turns out to be limiting
for most of the practical uses. Random search tries to generate different ligand
conformations using randomized schemes like genetic algorithm [14, 149].
Small-molecule ligands often interact with binding site presenting complementary features [150]. However, small size of such ligands at times has limited possibilities to interact with neutral binding pockets, because neutral binding site has
weak electrostatics interactions and hydrogen bonding capabilities [151]. Neutral
and wide open hydrophobic pockets can not present interactions strong enough to
portray desired high affinity for small-molecule ligands. On the other hand, peptide
ligands due to their flexibility can adopt a wide range of conformations to gain
higher affinity in such cases by making more hydrogen bond interactions and
through many weak hydrophobic interaction from several hot spots in the pocket
[151, 152].
3.5 Is Estimate of Binding Affinity Sufficient?
In case of receptor binding processes, the stability of the binding is accounted by
difference of Gibbs free energy between bound and unbound states. The equilibrium dissociation constant K d which is ratio of unbinding process k off and binding
process k on is associated with thermodynamic properties of the reactants/product,
whereas the activation energy for the process influenced by kinetic properties [153].
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137
interaction features in binding site could provide complementarity for even structurally very similar ligands but provide different poses; several such cases have
been reviewed by Teague et al. [147]. Another case could be enthalpy–entropy
compensation due to receptor–ligand flexibility for different poses of ligand [147].
Although docking and scoring lack capability to account entropy, considering
receptor–ligand flexibility in docking can be a poor proxy for entropy to certain
extents.
3.4 Flexibility of Ligand Provides Complementarity
Generally, small molecules can adopt a number of conformations within few kcal/
mol energy gap from the global minimum conformation. Thus, a number of conformations of ligands are generated and docked into the receptor to seek optimal
complementarity between receptor-binding site and the ligand conformation to yield
most probable pose. Therefore, several conformation generation schemes which can
be broadly put in two groups, (a) systematic search and (b) random search, have been
suggested and are routinely employed in docking studies [148]. Systematic search
tries to generate all the conformation corresponding to the rotational states for the
rotatable bonds of the molecule, but exponential increase of the number of conformations of the molecule with number of rotatable bonds turns out to be limiting
for most of the practical uses. Random search tries to generate different ligand
conformations using randomized schemes like genetic algorithm [14, 149].
Small-molecule ligands often interact with binding site presenting complementary features [150]. However, small size of such ligands at times has limited possibilities to interact with neutral binding pockets, because neutral binding site has
weak electrostatics interactions and hydrogen bonding capabilities [151]. Neutral
and wide open hydrophobic pockets can not present interactions strong enough to
portray desired high affinity for small-molecule ligands. On the other hand, peptide
ligands due to their flexibility can adopt a wide range of conformations to gain
higher affinity in such cases by making more hydrogen bond interactions and
through many weak hydrophobic interaction from several hot spots in the pocket
[151, 152].
3.5 Is Estimate of Binding Affinity Sufficient?
In case of receptor binding processes, the stability of the binding is accounted by
difference of Gibbs free energy between bound and unbound states. The equilibrium dissociation constant K d which is ratio of unbinding process k off and binding
process k on is associated with thermodynamic properties of the reactants/product,
whereas the activation energy for the process influenced by kinetic properties [153].
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
137