INTRODUCTION TO DOCKING

NARESH PANIGRAHI
 DEFINITION

• Molecular docking tries to predict the structure of the

intermolecular complex formed between two or more
constituent molecules.
• Molecular docking can be thought of as a problem of “lock-
and-key”, where one is interested in finding the correct
relative orientation of the “key” which will open up the
“lock” .
• Here, the protein can be thought of as the “lock” and the
ligand can be thought of as a “key”.
• Molecular docking may be defined as an optimization
problem, which would describe the “best-fit” orientation of
a ligand that binds to a particular protein of interest.
 Before Docking…
• First, this type of method we have to
 Confirm the target location first (target site)
 In the majority of the protein surface, to find
- Bind site
- Protein shape (shape) and surface
 characteristics, such as
 hydrophobic sites (H),
hydrogen bond donors (D) and
 acceptors (A)
-
• Basic questions:
- Where:
In such a large protein, the ligand to be able to
find a place for it.
- What:
When the compound obtained after docking
structure, its configuration (conformation) is
What?
- How:
Assessment of how good or bad??
 Docking methods

• A protein-ligand docking program consists of two essential

components, sampling and scoring.
 SAMPLING REFERS to the generation of putative ligand binding
orientations/conformations near a binding site of a protein and
can be further divided into two aspects,
 ligand sampling and
 protein flexibility.

 SCORING IS THE prediction of the binding tightness for

individual ligand orientations/conformations with a physical or
empirical energy function.
 The top orientation/conformation, namely the one with the
lowest energy score, is predicted as the binding mode.
Docking methods
 Protein Flexibility

• Ligand binding commonly induces protein

conformational changes (referred to as
“induced fit”), which range from local
rearrangements of side-chains to large domain
motions. Due to the large size and many
degrees of freedom of proteins, their flexibility
may be the most challenging issue in
molecular docking.
 Protein Flexibility

• Current methods to account for protein

flexibility can be grouped into four categories
 Soft Docking

• Soft docking is the simplest method which

considers protein flexibility implicitly. It works by
allowing for a small degree of overlap between the
ligand and the protein through softening the
Interatomic van der Waals interactions in docking
calculations.
• The advantages of soft docking are its
computational efficiency and easiness for
implementation. However soft docking can
account for only small conformational changes.
 Side-Chain Flexibility

• Many of the early attempts to incorporate certain

protein conformational changes into molecular docking
focused on side-chain flexibility, in which backbones
are kept fixed and side-chain conformations are
sampled.
• One of the earliest studies is the ligand docking
algorithm developed by Leach, in which discrete side-
chain flexibility is included by using a rotamer library15.
Since then, researchers have proposed many improved
techniques to incorporate continuous or discrete side-
chain flexibility in ligand docking 16-22.
 Molecular Relaxation

• The third type of methods account for protein flexibility by

firstly using rigid-body docking to place the ligand into the
binding site and then relaxing the protein backbone and side-
chain atoms nearby.
• Specifically, the initial rigid-body docking allows for atomic
clashes between the protein and the placed ligand
orientations/conformations in order to consider the protein
conformational changes.
• Then, the formed complexes are relaxed or minimized by Monte
Carlo (MC), Molecular Dynamic simulations, or other methods .
• The advantage of the molecular relaxation method is the
inclusion of certain backbone flexibility in addition to the side-
chain conformational changes.
 Docking of Multiple Protein Structures (Protein ensemble
docking)

• The most widely-used type of methods for

incorporating protein flexibility utilize an
ensemble of protein structures to represent
different possible conformational changes7-12.
• One of the earliest studies was done by Knegtel
et al.25, in which an averaged energy grid was
constructed by combining the energy grids
generated from individual experimentally-
determined protein structures using a weighting
scheme, followed by standard ligand docking.
 Ligand Sampling

• Ligand sampling is the most basic element in

protein-ligand docking. Given a protein target, the
sampling algorithm generates putative ligand
orientations/conformations (i.e., poses) around the
chosen binding site of the protein.
• Ligand sampling is the most successful area being
developed in protein-ligand docking.
• Roughly, there are three types of ligand sampling
algorithms:
 Shape Matching

• The shape matching method is one of the simplest

sampling algorithms which is often used in the early
stages of the docking process or in the first step of other
more advanced ligand sampling methods.
• It places the ligand using the criterion that the molecular
surface of the placed ligand must complement the
molecular surface of the binding site on the protein.
• Therefore, how to quickly place the ligand in the binding
site with a good shape complementarity is the goal of the
shape matching algorithm. Examples of docking programs
that use shape matching include DOCK, FRED, FLOG,
EUDOC, LigandFit, Surflex, MS-DOCK, and MDock.
 Systematic Search

• Systematic search algorithms are normally used

for flexible-ligand docking, which generate all
possible ligand binding conformations by
exploring all degrees of freedom of the ligand.
• There are three types of systematic search
methods:
• EXHAUSTIVE SEARCH,
• FRAGMENTATION AND
• CONFORMATIONAL ENSEMBLE.
 EXHAUSTIVE SEARCH METHODS
• The most straightforward systematic
algorithms are exhaustive search methods, in
which flexible-ligand docking is performed by
systematically rotating all possible rotatable
bonds of the ligand at a given interval.
• Glide and FRED are two
• typical examples of this
• type of hierarchical
• sampling methods.
 FRAGMENTATION METHODS
• In fragmentation methods, the ligand is first
divided into different rigid parts/fragments.
• Then, the ligand binding conformation is
incrementally grown by placing one fragment at a
time in the binding site or by docking all the
fragments into the binding site and linking them
covalently.
• DOCK, LUDI, FlexX, ADAM, and eHiTs are example
docking programs that use fragmentation
methods.
 conformational ensemble methods26
• In conformational ensemble methods26, ligand
flexibility is represented by rigidly docking an
ensemble of pre-generated ligand conformations
with other programs such as OMEGA (OpenEye
Scientific Inc, NM).
• Then, ligand binding modes from different docking
runs are collected and ranked according to their
binding energy scores.
• Examples of the conformational ensemble methods
for docking include FLOG, DOCK3.5, PhDOCK, MS-
DOCK, MDock, and Q-Dock .
 Stochastic Algorithms6

• In stochastic algorithms, ligand binding orientations and

conformations are sampled by making random changes
to the ligand at each step in both the conformational
space and the translational/rotational space of the
ligand, respectively.
• The random change will be accepted or rejected
according to a probabilistic criterion.
• There are four types of stochastic algorithms:
• 1) Monte Carlo (MC) methods,
• 2) evolutionary algorithms (EA),
• 3)Tabu search methods, and
 Monte Carlo (MC) methods
• In a Monte Carlo method, the probability to accept a random
change is calculated by using the following Boltzmann probability
function:
•
•

•
• Where E0 and E1 stand for the energy scores of the ligand before
and after the random change, respectively, kB is the Boltzmann
constant, and T is the absolute temperature of the system. The
docking programs that use the MC methods include DockVision,
ICM, QXP, Prodock, and MCDOCK .
 Evolutionary algorithms (EAs)
• Evolutionary algorithms (EAs) search for the
correct ligand binding mode based on the idea
from the evolutionary process in biological
systems.
• The most popular type of EAs is the genetic
algorithms (GAs). GOLD, AutoDock, DIVALI,
DARWIN, MolDock, PSI-DOCK, FLIPDock, Lead
finder, and EADock are the examples that have
implemented evolution algorithms.
 Genetic algorithms
• Genetic algorithms and evolutionary programming are
quite suitable for solving docking problems because of
their usefulness in solving complex optimization problems.
• The process of applying genetic algorithms starts with
encoding the variables, i.e the degrees of freedom, into a
"genetic code", e.g. binary strings.
• Then a random initial population of solutions is created.
Genetic operators are then applied to this population
leading to a new population. This new population is then
scored and ranked, and using "the survival of the fittest",
their probabilities of getting to the next iteration round
depends on their score.
 Tabu search algorithms
• These methods are based on stochastic processes, in which
new states are randomly generated from an initial state
(referred to as the current solution).
• These new solutions are then scored and ranked in ascending
order.
• The best new solution is then chosen as the new current
solution and the same process is then repeated again.
• To avoid loops and ensure diversity of the current solution a
tabu list is used. This list acts as a memory.
• It contains information about previous current solutions and a
new solution is rejected if it reminds a previous solution too
much. An example of docking algorithm using tabu search is
PRO_ LEADS.
 Swarm optimization (SO) algorithms
• Swarm optimization (SO) algorithms attempt
to find an optimal solution in a search space
by modeling swarm intelligence.
• In the method, movements of a ligand mode
through the search space are guided by the
information of the best positions of its
neighbors.
• Examples of docking programs that use swarm
optimization algorithms include SODOCK,
Tribe-PSO, PSO@Autodock , and PLANTS.
 Scoring Functions

• The scoring function is a key element of a protein-ligand

docking algorithm, because it directly determines the
accuracy of the algorithm.
• Speed and accuracy are the two important aspects of a
scoring function. An ideal scoring function would be both
computationally efficient and reliable.
• Numerous scoring functions have been developed in the
past decades and can be grouped into three basic
categories according to their methods of derivation:
• Force field scoring functions,
• Empirical scoring functions and
• Knowledge-based scoring functions.
 Force Field Scoring Functions
• Force field (FF) scoring functions are based on decomposition
of the ligand binding energy into individual interaction terms
such as
• van der Waals (VDW) energies, electrostatic energies, bond
stretching/bending/torsional energies, etc.,
• using a set of derived force-field parameters such as AMBER or
CHARMM force fields.
• One of the major challenges in FF scoring functions is how to
account for the solvent effect. The simplest method is to use a
distance-dependent dielectric constant Є(rij) such as the force
field scoring function in DOCK :
•
 Empirical Scoring Functions
• In empirical scoring functions, the binding energy score of a
complex is calculated by summing up a set of weighted empirical
energy terms such as VDW energy, electrostatic energy,
hydrogen bonding energy, desolvation term, entropy term,
hydrophobicity term, etc.

• Where {ΔGi} represent individual empirical energy terms, and

the corresponding coefficients {Wi} are determined by
reproducing the binding affinity data of a training set of protein-
ligand complexes with known three-dimensional structures,
using least squares fitting36-45. Compared to the force field scoring
functions, the empirical scoring functions are normally much
more computationally efficient due to their simple energy terms.
 EXAMPLES OF EMPIRICAL SCORING
FUNCTIONS.
• GlideScore,
• SYBYL/F-Score,
• LigScore,
• LUDI, SCORE,
• X-Score,
• ChemScore,
• MedusaScore ,
• AIScore, and
• SFCscore
are examples of empirical scoring functions.
 Knowledge-Based Scoring Functions
• Knowledge-Based Scoring Functions
• The potential parameters of knowledge-based scoring functions are directly
derived from the structural information in experimentally determined
protein-ligand complexes. The principle behind knowledge-based scoring
functions is the potential of mean force, which is defined by the inverse
Boltzmann relation

• where kB is the Boltzmann constant, T is the absolute temperature of the

system, ρ(r) is the number density of the protein-ligand atom pair at distance
r in the training set, and ρ*(r) is the pair density in a reference state where
the interatomic interactions are zero. After the potential parameters w(r) is
derived, the energy of ligand binding for a given complex is simply the sum
of the interaction terms for all the protein-ligand atom pairs in the complex.
Examples include DrugScore, SMoG, BLEEP, GOLD/ASP,
MScore, and KScore.