Basics Of Molecular Docking

BASICS OF
~MOLECULAR DOCKING~
SATARUPA DEB
ROLL- 10

Docking is a structure-based technique which attempts
to find the “best” match, between two molecules.

WHAT IS MOLECULAR DOCKING????
• In the field of molecular modeling, docking is a method which predicts
the preferred orientation of one molecule to a second when bound to
each other to form a stable complex.
• Knowledge of the preferred orientation in turn may be used to predict
the strength of association or binding affinity between two molecules
using for example scoring functions.
RECEPTOR LIGAND
LIGAND-RECEPTOR
COMPLEX

WHY IS DOCKING IMPORTANT?
 Signal Transduction :- The associations between biologically relevant molecules such
as proteins, nucleic acids, carbohydrates, and lipids play a central role in signal
transduction. Furthermore, the relative orientation of the two interacting partners may
affect the type of signal produced (e.g., agonism vs antagonism). Therefore docking is
useful for predicting both the strength and type of signal produced.
Drug-Designing:- Docking is frequently used to predict the binding orientation
of small molecule drug candidates to their protein targets in order to in turn predict
the affinity and activity of the small molecule. Hence docking plays an important role in
the rational design of drugs.

Receptor or host or lock: The "receiving" molecule, most commonly a protein or other
biopolymer.
Ligand or guest or key: The complementary partner molecule which binds to the receptor.
Ligands are most often small molecules but could also be another biopolymer.
Docking: Computational simulation of a candidate ligand binding to a receptor.
Binding mode: The orientation of the ligand relative to the receptor as well as the
conformation of the ligand and receptor when bound to each other.
Pose : A candidate binding mode.
Scoring : The process of evaluating a particular pose by counting the number of favorable
intermolecular interactions such as hydrogen bonds and hydrophobic contacts.
Ranking : The process of classifying which ligands are most likely to interact favorably to a
particular receptor based on the predicted free-energy of binding.
DOCKING GLOSSARY

DEFINITION OF THE PROBLEM
One can think of molecular docking as a problem of “lock-and-key”, in which one
wants to find the correct relative orientation of the “key” which will open up
the “lock” (where on the surface of the lock is the key hole, which direction to turn the
key after it is inserted, etc.)
 However, since both the ligand and the protein are flexible, a “hand-in-
glove” analogy is more appropriate than “lock-and-key”. During the course of the
docking process, the ligand and the protein adjust their conformation to achieve an
overall "best-fit" and this kind of conformational adjustment resulting in the overall
binding is referred to as "induced-fit“.

DOCKING APPROACHES
SHAPE COMPLEMENTARITY:- One approach uses a matching technique that
describes the protein and the ligand as complementary surfaces.
SIMULATION:- The second approach simulates the actual docking process in which
the ligand-protein pairwise interaction energies are calculated. Both approaches have
significant advantages as well as some limitations.
CALCULATE:-
Hydrophilic and hydrophobic
interactions.
Hydrogen bond donated.
Hydrogen bond accepted.
Ligand orientation with best
complementarity score.
Binding affinities.
Ionic interaction.
Aromatic Interaction.
Vander Waals’ forces
Electrostatic forces
Free energies.

STEPS OF DOCKING
Step 1: Start with Crystal Co-ordinates with target receptor.
For example,
-HIV-1 protease is the target receptor
- Aspartyl groups are its active sites

Step 2: Generate molecular surface for receptors.

Step 3: Generate spheres to fill the active site of the
receptor: The spheres become potential locations for ligand
atoms.

Step 4: Sphere centres are then matched with the
ligand atoms, to determine possible orientations for the
ligand.
Three scoring schemes:
o Shape scoring,
o Electrostatic scoring and
o Force-field scoring.
Step 5: Find the top scoring or the best ranking.

APPLICATIONS OF MOLECULAR DOCKING
Determination of the lowest free energy structures for the receptor-ligand
complex.
Calculate the differential binding of a ligand to two different macromolecular
receptors.
Study the geometry of a particular complex.
Propose modification of lead molecules to optimize potency or other properties.
De novo design for lead generation.
Library design.
Screening for the side effects that can be caused by interactions with other
molecules.
To check the specificity of the potential drug against homologous proteins
through docking.
Docking is also a widely used tool for predicting protein-protein interaction.
Knowledge of the molecular associations aid in understanding a variety of
pathways taking place in the living and in revealing of the possible pharmacological
targets.
Protein-ligand docking can also be used to predict pollutants that can be
degraded by enzymes.

COMMON SOFTWARES USED FOR DOCKING PURPOSE
1. UCSF DOCK- USA (1988)

2. AUTODOCK- USA (1990)
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.
Current distributions of AutoDock consist of two generations of software: AutoDock 4
and AutoDock Vina.

3. FlexX- Germany (1996)
Receptor is treated as rigid.
Incremental construction algorithm:
Break Ligand up into rigid fragments
Dock fragments into pocket of receptor
Reassemble ligand from fragments.
Energy conformations

4. GOLD- UK (1995)
Performs automated docking with
full acyclic ligand flexibility, partial
cyclic ligand flexibility and partial
protein flexibility in and around
active site.
Scoring: includes H-bonding term,
pairwise dispersion potential
(hydrophobic interactions),
molecular and mechanics term for
internal energy

OTHER SOFTWARES
AADS- India (2011)
ADAM- Japan (1994)
BetaDock- South Korea (2011)
DARWIN- USA (2000)
DIVALI- USA (1995)
DockVision- Canada (1992)
EADock- Switzerland (2007)

Understanding the ruling principles whereby protein receptors recognize,
interact, and associate with molecular substrates and inhibitors is of
paramount importance in drug discovery efforts. Protein-ligand docking
aims to predict and rank the structure(s) arising from the association
between a given ligand and a target protein of known 3D structure. Despite
the breathtaking advances in the field over the last decades and the
widespread application of docking methods, several downsides still exist. In
particular, protein flexibility-a critical aspect for a thorough understanding
of the principles that guide ligand binding in proteins-is a major hurdle in
current protein-ligand docking efforts that needs to be more efficiently
accounted for. In this review the key concepts of protein-ligand docking
methods are outlined, with major emphasis being given to the general
strengths and weaknesses that presently characterize this methodology.
Despite the size of the field, the principal types of search algorithms and
scoring functions are reviewed and the most popular docking tools are
briefly depicted.
CONCLUSION

REFERENCES
1. Lengauer T, Rarey M (1996). "Computational methods for biomolecular
docking". Curr. Opin. Struct. Biol. 6 (3): 402–6. doi:10.1016/S0959-440X(96)80061-
3. PMID 8804827
2. Jorgensen WL (1991). "Rusting of the lock and key model for protein-ligand
binding".Science 254 (5034): 954–5. doi:10.1126/science.1719636. PMID 1719636
3. http://www.crcnetbase.com/doi/abs/10.1201/9781420028775.ch3
4. http://www.ccdc.cam.ac.uk/Solutions/GoldSuite/Pages/GOLD.aspx
5. Wei BQ, Weaver LH, Ferrari AM, Matthews BW, Shoichet BK (2004). "Testing a
flexible-receptor docking algorithm in a model binding site". J. Mol. Biol. 337 (5):
1161–82.doi:10.1016/j.jmb.2004.02.015. PMID 15046985
6. http://autodock.scripps.edu/
7. http://www.ibms.kmu.edu.pk/sites/ibms.kmu.edu.pk/files/downloads/Dr.%20Abdu
l%20Wadood.pdf

Basics Of Molecular Docking

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Basics Of Molecular Docking