Molecular Docking

VIRTUAL SCREENING

Anjaney Sharma
 INTRODUCTION
Docking is an attempt to find the best matching between two molecules.
A more serious definition.
Docking is a method which predicts the preferred orientation of one ligand when
bound in an active site to form a stable complex.

Docking of small molecule ligand (brown) with a protein receptor (green) to produce
a complex.
 MOLECULAR DOCKING
Aim:
To achieve an optimized conformation for both receptor and ligand & the
relative orientation between protein and ligand such that the free energy of the
overall system is minimized
Successful docking methods search high-dimensional spaces effectively and
use a scoring function that correctly ranks candidate dockings.
 types of docking

Rigid Docking (Lock and Key)

In rigid docking, the internal geometry of both the receptor and ligand are
treated as rigid.

Flexible Docking (Induced fit)

An enumeration on the rotations of one of the molecules (usually smaller
one) is performed. Every rotation the energy is calculated; later the most
optimum pose is selected.
Docking can be between.

Protein - Ligand

Protein Protein

Protein Nucleotide
 TYPES OF INTERACTIONS
Electrostatic forces - Forces with electrostatic origin are due to the charges residing in
the matter.

Electrodynamics forces - The most widely known is probably the van der Waals
interaction.

Steric forces - These are caused by entropy. For example, in cases where entropy is
limited, there may be forces to minimize the free energy of the system.

Solvent-related forces These are due to the structural changes of the solvent. These
structural changes are generated, when ions, colloids, proteins etc, are added into the
structure of solvent. The most commonly are Hydrogen bond and hydrophobic
interactions
A typical docking workflow

TARGET LIGAND
SELECTION SELECTION

TARGET LIGAND
PREPARATION PREPARATION

DOCKING

EVALUATING DOCKING
RESULT
 Softwares
SANJEEVINI IIT Delhi (www.scfbio-iitd.res.in/sanjeevini/sanjeevini.jsp)

GOLD University of Cambridge ,UK

(www.ccdc.cam.ac.uk/Solutions/GoldSuite/Pages/GOLD.aspx)

AUTODOCK - Scripps Research Institute,USA (autodock.scripps.edu/)

GemDock(Generic Evolutionary Method for Molecular Docking) - A tool, developed

by Jinn-Moon Yang, a professor of the Institute of Bioinformatics, National Chiao Tung
University, Taiwan (gemdock.life.nctu.edu.tw/dock/)

Hex Protein Docking - University of Aberdeen, UK (hex.loria.fr/)

GRAMM (Global Range Molecular Matching) Protein docking - A Center for

Bioinformatics, University of Kansas, USA
(www.bioinformatics.ku.edu/files/vakser/gramm/)
 Automatic docking
A perfect molecular docking technique:

Reasonable computation time.

The global minimum of the ligand/target interaction energy is reached.
The calculated free energies matches the experimental ones.
Experimental interaction patterns observed in XRay complexes are
identical.

Generally the molecular docking simulation can be shared in two steps.

DOCKING

Searching algorithm: Scoring function:

- Conformational exploration - Energy quantification
- Several possible docking poses - Ranking of docking poses
 Automatic docking
Algorithms and methods

. Grid method

A box is drawn on the protein

macromolecule. Therefore, the interaction
will be explored only on this box. This
drastically limits the computational time.

Beware:
o If the box is too small, docking will be false

o If the box is too large, exploration must be

more intensive and could provides strange
"false positive" ligand conformations
 Scoring
Aims to describe and quantify the association.

Purpose:

Quick computation

Able to compare results with

experimental data

Able to rank the ligands

 Virtual screening
Instead of making molecular docking for a small set of defined ligands this
computation is extended to a large database.

The compounds which will have the best ranks will be purchased and
biologically tested.

Three major steps:

1. Ligand database. We should use a preferable database.
2. Molecular docking. Even if your database is full of good compounds if
you are not able to correctly dock each one... You will have nothing at
the end.
3. Ranking. Even if the two previous steps were correctly made, if you are
not able to meaningfully rank the ligands... You will have nothing at the
end.
 General conclusions
Molecular docking is an efficient method to
predict the structural interaction of an organic
molecule inside a biomacromolecule binding
site.

However, molecular docking has a weakness

for the determation of the interaction energy
(scoring function).

Generally, molecular docking calculations and

their applications don't give an unique solution
but rather several solutions.

Molecular docking is mainly applied for the

drug-design and get many success.
Thank You