Bioinformatics Tools Training Program

Molecular docking is an attractive scaffold to understand drugbiomolecular interactions for the
rational drug design and discovery, as well as in the mechanistic study by placing a molecule
(ligand) into the preferred binding site of the target specific region of the DNA/protein (receptor)
mainly in a non-covalent fashion to form a stable complex of potential efficacy and more
specificity. The information obtained from the docking technique can be used to suggest the binding
energy, free energy and stability of complexes.

The main objective of molecular docking is to attain ligand-receptor complex with optimized
conformation and with the intention of possessing less binding free energy.
Practical application of molecular docking requires data bank for the search of target with proper
PDB format and a methodology to prepare ligand as a PDB file. TThese tools provide the
organization to ligands based upon their ability to interact with given target proteins/DNA.
Molecular docking of small molecules to a target includes a pre-defined sampling of possible
conformation of ligand in the particular groove of target in an order to establish the optimized
conformation of the complex. This can be made possible using scoring function of software.

Lock and key hypothesis
Enzymes are folded into complex 3D shapes that allow smaller molecules to fit into them. The
place where these molecules fit is called the active site.
In the lock and key hypothesis, the shape of the active site matches the shape of its substrate
molecules. This makes enzymes highly specific. Each type of enzyme can usually catalyse only one
type of reaction (some may catalyse a few types of reactions).

Induced Fit Model
Active sites in the uninduced enzyme are shown schematically with rounded contours. Binding of
the first substrate (gold) induces a physical conformational shift (angular contours) in the protein
that facilitates binding of the second substrate (blue), with far lower energy than otherwise required.
When catalysis is complete, the product is released, and the enzyme returns to its uninduced state.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is
mainly determined by the shape and chemical characteristics of their active site—the region of the
enzyme that binds to the substrate.

According to the induced-fit model of enzyme activity, this binding changes the conformation—or
shape—of both the enzyme and the substrate. This brings the substrate closer to the higher energy
transition state needed for the reaction to occur, for instance, by weakening its bonds so that it can
more readily react. Enzymes may also speed up a reaction by creating conditions within the active
site that are more conducive for the reaction to proceed than the surrounding cellular environment.

Approaches of Molecular Docking
Simulation approach
Here the ligand and target is being separated by physical distance and then ligand is allowed to bind
into groove of target after “definite times of moves” in its conformational space. The moves involve
variations to the structure of ligand either internally (torsional angle rotations) or externally
(rotations and translations). The ligand in every move in the conformational limit releases energy, as
“Total Energy”. This approach is more advantageous in the sense that it is more compatible to
accept ligand flexibility.

Shape complementarity approach
This approach employs ligand and target as surface structural feature that provides their molecular
interaction. Here the surface of target is shown with respect to its solvent-accessible surface area
and ligand’s molecular surface is showed in terms of matching surface illustration. The
complementarity between two surfaces based on shape matching illustration helps in searching the
complementary groove for ligand on target surface.

Applications of Molecular Docking
Molecular docking can demonstrate the feasibility of any biochemical reaction as it is carried out
before experimental part of any investigation. Such type of information may provide a raw material
for the rational drug designing. Some of the major applications of molecular docking are described
below: –

Lead optimization
Molecular docking can predict an optimized orientation of ligand on its target. It can predict
different binding modes of ligand in the groove of target molecule. This can be used to develop
more potent, selective and efficient drug candidates.

Hit identifications
Docking in combination with scoring function can be used to evaluate large databases for finding
out potent drug candidate in silico, which can target the molecule of interest.

Drug-DNA interaction
Molecular docking plays a prominent role in the initial prediction of drug’s binding properties to
nucleic acid. This information establishes the correlation between drug’s molecular structure and its
cytotoxicity. Keeping this in view, medicinal chemists are constantly putting their efforts to
elucidate the underlying anticancer mechanism of drugs at molecular level by investigating the
interaction mode between nucleic acid and drugs.