for the multitarget structure-based designing like bacterial multidrug efflux pump
and AcrAB-TolC pump [143].
3.3 Why Different Poses?
While docking of different chemical ligand at the known active site, one can
generate different orientation for the same ligand, which is defined as “pose” due to
the fact that many features available in the active sites may or may not be satisfied
by the complementary features available in docked ligand. Such variations in
interaction between protein and ligand may also occur due to the flexibility of active
site residues [14].
Lock-and-key: The lock-and-key model of enzyme substrate interaction proposed
by Emil Fisher in 1894. It assumes enzyme-binding site as a cavity with specific set
of shape and physicochemical interaction features analogous to the key-hole of a
lock, while ligands are potential molecules which possess shape and interaction
feature of key, i.e., complementarity [39]. Generally, receptor–ligand interactions
are considered to imitate this model during binding. This model was the early
motivation for development of docking and scoring studies. However, many
interactions associated with the flexibility of ligand upon binding to receptors and
vice versa; hence, other models are proposed [36].
Induced fit: The idea of induced fit model (Fig. 7) of binding occurred as many
cases the binding site of the protein undergoes subtle arrangements of key residues
side chain orientations or conformational changes sensing the presence of ligand in
the vicinity under the influence of its interaction fields [144]. For example,
drug-target aldose reductase undergoes large conformation change during binding
of ligand [79]. Several other cases of this model of ligand–receptor binding are
discussed in the section Protein Flexibility.
Conformational selection: This model proposes that the receptor maintains an
ensemble of conformations in equilibrium, rather than being into some particular
conformational state before binding (as in lock-and-key) or changing conformation
sensing the ligand (as in induced fit), whereas ligand binds to the conformation
presenting best complementarity at the binding site [39]. For example, BACE-1
binding to and showing significant activity only at narrow pH range 4–5 is actually
in equilibrium of at least three Tyr-inhibited, binding-competent and Gln-inhibited
significant conformations [96]. However, only binding-competent conformation
being conformationally compatible for binding has the highest population at the
specified activity pH range 4–5, but the population of these conformation at pH < 4
or pH > 5 is decreased and hence the activity [96]. Another model known as
conformational isomerism is found in the literature [14] and has been a special case
of the conformational selection, where one or more conformational isomers of the
receptor exist in equilibrium and ligand binds to only conformationally compatible
isomeric form of the receptor, and binding shifts the conformational equilibrium in
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
135
and AcrAB-TolC pump [143].
3.3 Why Different Poses?
While docking of different chemical ligand at the known active site, one can
generate different orientation for the same ligand, which is defined as “pose” due to
the fact that many features available in the active sites may or may not be satisfied
by the complementary features available in docked ligand. Such variations in
interaction between protein and ligand may also occur due to the flexibility of active
site residues [14].
Lock-and-key: The lock-and-key model of enzyme substrate interaction proposed
by Emil Fisher in 1894. It assumes enzyme-binding site as a cavity with specific set
of shape and physicochemical interaction features analogous to the key-hole of a
lock, while ligands are potential molecules which possess shape and interaction
feature of key, i.e., complementarity [39]. Generally, receptor–ligand interactions
are considered to imitate this model during binding. This model was the early
motivation for development of docking and scoring studies. However, many
interactions associated with the flexibility of ligand upon binding to receptors and
vice versa; hence, other models are proposed [36].
Induced fit: The idea of induced fit model (Fig. 7) of binding occurred as many
cases the binding site of the protein undergoes subtle arrangements of key residues
side chain orientations or conformational changes sensing the presence of ligand in
the vicinity under the influence of its interaction fields [144]. For example,
drug-target aldose reductase undergoes large conformation change during binding
of ligand [79]. Several other cases of this model of ligand–receptor binding are
discussed in the section Protein Flexibility.
Conformational selection: This model proposes that the receptor maintains an
ensemble of conformations in equilibrium, rather than being into some particular
conformational state before binding (as in lock-and-key) or changing conformation
sensing the ligand (as in induced fit), whereas ligand binds to the conformation
presenting best complementarity at the binding site [39]. For example, BACE-1
binding to and showing significant activity only at narrow pH range 4–5 is actually
in equilibrium of at least three Tyr-inhibited, binding-competent and Gln-inhibited
significant conformations [96]. However, only binding-competent conformation
being conformationally compatible for binding has the highest population at the
specified activity pH range 4–5, but the population of these conformation at pH < 4
or pH > 5 is decreased and hence the activity [96]. Another model known as
conformational isomerism is found in the literature [14] and has been a special case
of the conformational selection, where one or more conformational isomers of the
receptor exist in equilibrium and ligand binds to only conformationally compatible
isomeric form of the receptor, and binding shifts the conformational equilibrium in
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
135