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Molecular Docking
• Molecular recogni,on is the ability of biomolecules to recognize other biomolecules and
selec4vely interact with them in order to promote fundamental biological events such as
transcrip4on, transla4on, signal transduc4on, transport, regula4on, enzyma4c catalysis, viral and
bacterial infec4on and immune response.
• Molecular docking is the process that involves placing molecules in appropriate configura4ons to
interact with a receptor. Molecular docking is a natural process which occurs within seconds in a
cell.
• In molecular modeling the term “molecular docking” refers to the study of how two or more
molecular structures fit together.
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• A more serious definition…
• Docking is a method which predicts the preferred orientation of one molecule to a second
when bound to form a stable complex with overall minimum energy.
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Lock and Key
• Finding the correct rela4ve orienta4on of the “key” which will open up the “lock”.
• The protein can be thought of as the “lock” and the ligand can be thought of as a “key”.
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Docking can be between …
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Aim
• To achieve an op4mized conforma4on for both receptor and ligand & the rela4ve orienta4on
between protein and ligand such that the free energy of the overall system is minimized.
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“Pose” and “Binding Mode”
• A "pose" is a term widely adopted for describing the geometry of a par4cular complex (also called
"binding mode").
• It refers to a precise configura4on which is characterized not only by the rela4ve orienta4on of
the docked molecules but also their respec4ve conforma4ons.
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• Successful docking methods search high-dimensional spaces effectively and use a scoring function
that correctly ranks candidate dockings.
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Three Components of Docking Software
• Docking soKware can be categorized based on the following criteria:
1. Molecular representa4on - a way to represent structures and proper4es (atomic, surface,
grid representa4on)
2. Searching algorithm - an efficient search algorithm that decides which poses to generate
3. Scoring method - a method to assess the quality of docked complexes
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1. Molecular representaFon
• There are three representations commonly used in docking programs:
• The atomic representation (the most common) - each atom is characterized by its
coordinates and atom-type
• The surface representation
• The grid representation
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2. Search Algorithm
• Determine all possible op4mal conforma4on for a given complex (protein-ligand/ protein-
protein).
• Output à several possible docking poses
• Conforma4onal search strategies include
Ø Systema4c/ stochas4c torsional searches about rotatable bonds
Ø Molecular dynamic simula4ons
Ø Gene4c algorithms to evolve new low energy conforma4ons
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3. Scoring FuncFon
• Output à ranking of docking poses
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3. Scoring FuncFon
• Scoring methods aim at assessing the quality of docked complexes and guiding the docking
algorithm
• The binding process that leads to the formation of a complex between a ligand and its receptor is
controlled by several factors including:
1. The interaction energies between the two molecules
2. The desolvation and solvation energies associated with the interacting molecules
3. The entropic factors that occur upon binding
• The final free energy of binding will depend on the overall balance of these factors
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Interaction Energies
• The interac4on forces between two molecules can be divided into:
• Electrosta4c interac4ons
• Hydrogen bond interac4ons
• Van der Waals interac4ons
• Hydrophobic forces
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Molecular Docking
DesolvaFon Energies
• The binding of a ligand to a protein is a complex process influenced by desolvation and solvation
phenomena where the interacting entities become partially desolvated.
• This thermodynamically driven chain of events leads to the formation of favorable interactions
between the ligand and the protein where hydrophobic contacts are the driving forces:
hydrophobic moieties associate together to reduce the interactions with the surrounding water.
• Another important energy term is electrostatic interaction between charged atoms and water
molecules.
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Entropic Effects
• The flexibility of the molecules and the consequences in terms of entropy can have a significant
impact on the binding energy of a ligand.
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Molecular Docking
Calculation of the Binding Energies
• The binding energy ΔGbinding is the energy required to separate a complex into separate parts
(protein and ligand). It is defined as the difference between the energy of the associated (bound)
form (Ecomplex) and that of the separated (unbound) molecules (Eprotein and Eligand).
• A complex has a lower poten4al energy than its cons4tuent parts. This is what keeps them
together.
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Force-Field CalculaFons
• Molecular mechanics can be used to estimate the internal energy of the system, which makes it
useful for calculating ΔG
• The total energy of a system is described as the sum of the independent terms of the force field.
• The energies obtained by force field methods can be used directly to approximate free energies of
binding.
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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)
• The basic idea is that in the recogni4on process, both ligand
and target mutually adapt to each other through small
conforma4onal changes, un4l an op4mal fit is achieved.
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Molecular Flexibility in Protein-Ligand Docking
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Key Stages in Docking
• Target/Receptor selection and preparation
• Ligand selection and preparation
• Docking
• Evaluating docking results
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Key Stages in Docking
• Receptor selec*on and prepara*on
• Building the Receptor
• The 3D structure of the receptor should be considered which can be downloaded from PDB.
• The available structure should be processed.
• The receptor should be biologically ac4ve and stable.
• Iden,fica,on of the Ac,ve Site
• The ac4ve site within the receptor should be iden4fied.
• The receptor may have many ac4ve sites but the one of the interest should be selected.
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Key Stages in Docking
• Ligand selection and preparation
• Ligands can be obtained from various databases like ZINC, PubChem or can be sketched using tools
like Chemsketch.
• Docking
• The ligand is docked onto the receptor and the interactions are checked. The scoring function
generates score, depending on which the best fit ligand is selected.
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Importance
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ApplicaFons
• Virtual screening (hit identification)
• docking with a scoring function can be used to quickly screen large databases of potential
drugs in silico to identify molecules that are likely to bind to protein target of interest.
• Drug Discovery (lead optimization)
• docking can be used to predict in where and in which relative orientation a ligand binds to a
protein (binding mode or pose). This information may in turn be used to design more potent
and selective analogs.
• Bioremediation
• Protein ligand docking can also be used to predict pollutants that can be degraded by
enzymes.
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