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of APPLIED GENETICS

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Molecular Docking


Molecular docking is one of the fastest growing applications in
computational biology and drug discovery. Molecular docking is used to
predict the structure of the intermolecular complex formed between two
or more molecules. The most interesting case is the protein-ligand
interaction, because of its applications in medicine. Ligand is a small
molecule, which interacts with protein's binding sites. Binding sites are
areas of protein known to be active in forming of compounds. The ability
of a protein to interact with small molecules governs a significant part of
the proteins dynamics, which may enhance / inhibit its biological
function. This plays an important role in the rational design of drugs.

To perform molecular docking there are good number of software
available and are mainly used in drug industry. The most important
application of docking software is virtual screening. In virtual screening
the most interesting and promising molecules are selected from an
existing database for further research. This procedure not only reduces
the time in drug discovery process but also expenses. Beyond protein-
ligand interaction, docking procedure can also be applied to study
protein-protein interaction and protein-nucleic acid interaction.

In Molecular docking procedure when studying the structure of matter
(either protein or ligand) the physical parameters are important along
with the biological concept. The most important physical parameter is
quantum mechanics to study the structure of objects and forces like
electrostatics, electrodynamic, steric and solvent related forces to
understand the interaction.


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Definition of Molecular Docking
In general docking means hooking the ship to ship yard for loading,
unloading, or repairs. Molecular docking is a procedure to study how two
molecules (protein/DNA /small molecules) interact each other and to
interpret what level the affinity between the two molecules.

Molecular Docking Problem

Molecular docking procedure answer the following questions.
Whether two molecules (protein /DNA /organic molecule) interact
each other?. The molecules should be in 3D conformations (atomic
coordination files)
If the interation is yes (if they bind each other)
How strong is the binding affinity?
How does the molecule-molecule complex look like?

By answering these questions one can solve the problems like,
Protien-ligand docking
o Rigid-body docking
o Flexible docking
Protein-protein docking
Protein-DNA docking
DNA-ligand docking


Rigid and Flexible Docking
Generally protein-protein interactions differ from protein-ligand
interactions due to the small size of ligand. Because of their large size,
proteins are usually treated as rigid bodies. However, conformational
changes in the protein and the ligand are often necessary for a
successful docking process. That is why it must be clearly understood
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how drastic generalization the rigid body approach is. One of the goals in
current research is to be able to use flexible protein structure models.

Search Algorithm and Scoring Function in Docking
Molecular docking can be divided into two separate problems. The search
algorithm should create an optimum number of configurations that
include the experimentally determined binding modes. These
configurations are evaluated using scoring functions to distinguish the
experimental binding modes from all other modes explored through the
searching algorithm. A rigorous searching algorithm would go through all
possible binding modes between the two molecules. This is impossible
using normal computational approach and to solve this problem many
people have developed the search algorithms and scoring functions to
evaluate the binding affinity of two molecules.
Some common searching algorithms include

o Molecular Dynamics
o Monte Carlo Methods
o Genetic Algorithms
o Fragment-Based Methods
o Point Complementary Methods
o Distance Geometry Methods
o Tabu Searches
o Systematic Searches

Current docking methods utilize the scoring functions in one of two
ways.

1. The first approach uses the full scoring function to rank a protein-
ligand conformation. The system is then modified by the search
algorithm, and the same scoring function is again applied to rank
the new structure.
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2. In the alternative approach a two stage scoring function is used. A
reduced function is used in directing the search and a more
rigorous one is then used to rank the resulting structures.

Some common scoring functions are

o Force field methods
o Empirical free energy scoring functions
o Knowledge-based potential of mean force

Docking Software

There are good numbers of docking programs available commercially.
Despite the huge variety of available programs, no single program has
been able to become recognized as a standard. Apart from selecting the
right program for your applications, your knowledge about the concept is
very important. It also seems that some of the existing programs are
reaching a bit more mature state, since there seem to be an increasing
number of commercial solutions available. Docking programs are usually
sold in a package with other molecular design software.

Some of the docking software are mentioned below,

Autodock
AutoDock is a suite of automated docking tools. It is designed to predict
how small molecules, such as substrates or drug candidates, bind to a
receptor of known 3D structure. AutoDock uses Monte Carlo simulated
annealing and Lamarckian genetic algorithm (LGA) to create a set of
possible conformations. LGA is used as a global optimizer and energy
minimization as a local search method. Possible orientations are
evaluated with AMBER force field model in conjunction with free energy
scoring functions and a large set of protein-ligand complexes with known
protein-ligand constants.
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URL: http://autodock.scripps.edu/

DOCK
DOCK is one of the oldest and best-known ligand-protein docking
programs. The initial version used rigid ligands; flexibility was later
incorporated via incremental construction of the ligand in the binding
pocket. The DOCK is a fragment-based method using shape and
chemical complementary methods for creating possible orientations for
the ligand. With the release of DOCK 6, they have improved the
algorithm's ability to predict binding poses by adding new features like
force-field scoring enhanced by solvation and receptor flexibility.
URL: http://dock.compbio.ucsf.edu/

FlexX
FlexX is an extremely fast, robust, and highly configurable (FlexX-able)
computer program for predicting protein-ligand interactions. FlexX is a
fragment-based method using flexible ligands and rigid proteins. It uses
MIMUMBA torsion angle database for the creation of conformers. The
MIMUMBA is an interaction geometry database used to exactly describe
intermolecular interaction patterns. For scoring, the Boehm function
(with minor adaptations necessary for docking) is applied. There is an
extension of FlexX called FlexE with flexible receptors, which has shown
to produce better results with significantly lower running times.
URL: http://www.biosolveit.de/FlexX/

Gold
GOLD is a program for calculating the docking modes of small molecules
into protein binding sites. Gold has won a lot of new users during the
last few years because of its good results in impartial tests. It has a good
hit rate overall, however it somewhat suffers when dealing with
hydrophobic binding pockets. Gold uses genetic algorithm to provide
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docking of flexible ligand and a protein with flexible hydroxyl groups.
Otherwise the protein is considered to be rigid. This makes it a good
choice when the binding pocket contains amino acids that form hydrogen
bonds with the ligand. Gold uses a scoring function that is based on
favorable conformations found in Cambridge Structural Database and on
empirical results on weak chemical interactions.
URL: http://www.ccdc.cam.ac.uk/products/life_sciences/gold/

Hex 4.1
Hex is an interactive molecular graphics program for calculating and
displaying feasible docking modes of pairs of protein and DNA molecules.
Hex can also calculate small-ligand/protein docking (provided the ligand
is rigid), and it can superpose pairs of molecules using only knowledge of
their 3D shapes.
The main thing, which distinguishes Hex from other macromolecular
docking programs and molecular graphics packages is its use of
spherical polar Fourier correlations to accelerate the docking and
superposition calculations.

URL: http://www.csd.abdn.ac.uk/hex/