Understanding Molecular Docking in Bioinformatics

 
Session 12
 
Interaction Bioinformatics: Molecular
Docking
 
Methods of Bioinformatics
 
R
e
l
a
t
e
d
 
L
e
a
r
n
i
n
g
 
O
u
t
c
o
m
e
s
 
By the end of this session, students will be able to
:
To understand The 
docking
 analysis
 
O
u
t
l
i
n
e
 
1.
Molecular Docking Definition
2.
Theory of Enzyme
3.
Thermodynamics and Docking
4.
Tasks of Docking
5.
Practice of Docking
6.
Conclusion
 
Session 12
 
Interaction Bioinformatics: Molecular
Docking
Section number : 1
Molecular Docking Definition
 
Methods of Bioinformatics
 
Molecular Docking
 
 
W
h
a
t
?
 
In silico
 
(computer-based) approach
The approach 
is totally done in a computer
. Yet the data is not always
Identification of bound conformation
Check how your 
chemicals bind 
to each other. In which part? How is the
conformation?
Prediction of binding affinity
How strong 
the bond 
is?
Docking vs. (Virtual) Screening
Similar but 
not the same
 
 
Protein-Ligand
Docking
 
Protein-Protein
Docking
 
M
o
d
e
s
 
o
f
 
D
o
c
k
i
n
g
 
2 “Modes”:
Respective: How does your 
molecule bind? 
What is its mode of action? What
might be the 
reaction mechanism
?
Prospective: What compounds might be 
good leads
? What compound(s)
should you make?
 
D
o
c
k
i
n
g
 
a
p
p
r
o
a
c
h
e
s
 
 
i
n
 
a
 
n
u
t
s
h
e
l
l
 
Initially
 –Receptor (protein) and
ligand
 
rigid
Most current approaches 
–Receptor
rigid, ligand
 
flexible
Advanced approaches
–Receptor (to
a degree) and ligand
 
flexible
 
Fast, Simple
 
Slow, Complex
 
Session 12
 
Interaction Bioinformatics: Molecular
Docking
Section number : 2
Theory of Enzyme
 
Methods of Bioinformatics
 
K
e
y
-
l
o
c
k
 
T
h
e
o
r
y
 
Specific action of a protein with 
a single substrate 
(Postulated by Emil
Fischer in 1894)
Lock is enzyme, key is substrate
Only the 
CORRECT SIZE 
and 
CONFORMATION
 key (substrate) will fit
to The keyhole of the lock (enzyme)
 
I
n
d
u
c
e
d
 
F
i
t
 
T
h
e
o
r
y
 
Not
 
all
 
experimental
 
evidence
 
can
 
be
 
adequately
 
explained
 using t
he
 
key-
­‐lock
 
theory
Assumes
 
that
 
the
 
substrate
 
plays
 
a
 
role
 
in
 
determining
 
the
 
final
 
shape
 
of
the
 
enzyme
 
and
 
that
 
the
 
enzyme
 
is
 
PARTIALLY
 
FLEXIBLE
.
It explains some compound can bind but 
no reaction occurs
; enzyme is distorted
too much due to binding
Others are too small to induce proper alignment
Only the proper 
substrate can induce 
proper alignment to the active site
 
 
Both theories underline 
the different types of docking
Complexity on both receptor 
and ligand also play a
pivotal role
 
Session 12
 
Interaction Bioinformatics: Molecular
Docking
Section number : 3
Thermodynamics and Docking
 
Methods of Bioinformatics
 
M
o
l
e
c
u
l
a
r
 
R
e
c
o
g
n
i
t
i
o
n
 
The central phenomenon in biochemistry
Enzyme
 with substrate
Protein
 receptor and ligand
Antigen
 and antibody
Etc.
How to investigate those?
Molecular 
Docking
Free energy 
calculations
QM/MM 
(quantum mechanics/molecular mechanics) method
 
OUR FOCUS TODAY
 
S
o
m
e
 
d
e
f
i
n
i
t
i
o
n
s
 
f
i
r
s
t
 
pKd measures tightness of binding
pKi measures ability to inhibit
Gibbs free energy of binding
:
 
 
Mechanisms:
Competitive
 inhibition (most typical in docking)
Allosteric
 inhibition (inhibitors bind to different pocket to
inhibit enzyme)
Allosteric
 activation (activators bind to different pocket to
activate enzyme)
 
E
n
e
r
g
y
 
b
i
n
d
i
n
g
?
?
 
Molecular recognition based on 
enthalpy and
entropy
Enthalpy:
Direct interactions 
between ligand, solvent, proteins, ions
Ligand-protein
Ligand-solvent
Protein-solvent
Conformational changes 
during binding
 
E
n
e
r
g
y
 
b
i
n
d
i
n
g
?
?
 
Entropy
:
Rotational and translational entropy
Conformational entropy
Solvent reorganization (based on protein or ligand
hydrophobicity)
Vibrational entropy
 
Don’t worry, the software will
calculate for you, you just need to
know what is the energy meaning
 
Session 12
 
Interaction Bioinformatics: Molecular
Docking
Section number : 4
Task of Docking
 
Methods of Bioinformatics
 
W
h
a
t
 
i
s
 
d
o
c
k
i
n
g
 
e
x
a
c
t
l
y
?
 
Finding the right pose
 of ligand and protein!
Making difference between right and wrong docking
poses
Making difference 
between high and not so high affinity
compounds
 
3
 
t
a
s
k
s
 
o
f
 
M
o
l
e
c
u
l
a
r
 
D
o
c
k
i
n
g
 
 
U
s
a
g
e
 
Reproduce
 
the
 
binding
 
mode
 
of
 
x-­‐ray
 
ligand
Predicting
 
the
 
binding
 
mode
 
of
 
a
 
known
 
active
 
ligands
Predicting
 
the
 
binding
 
affinities
 
of
 
related
 
compounds
 
from
 
a
 
known
active
 
series
Identifying
 
new
 
ligands
 
using
 
virtual
 
screening
 
 
 
 
 
D
o
c
k
i
n
g
 
a
p
p
r
o
a
c
h
e
s
 
Initially
 –Receptor (protein) and ligand
 
rigid
Search the relative orientation of 2 molecules with the lowest energy
Conformational analysis needed for both molecules
Software: FLOG
Most current approaches 
–Receptor rigid, ligand
 
flexible
Need several protein structures
Software: GOLD, Autodock, GLIDE
Advanced approaches
–Receptor (to a degree) and ligand
 
flexible
Induced-fit method (GLIDE, MOE)
Sidechain flexibility (Surf-flex, GOLD, Autodock)
 
D
o
c
k
i
n
g
 
w
o
r
k
f
l
o
w
 
Binding mode prediction
Search algorithm to find the docking complex structure by scoring function
Consume lots of CPU-time
Binding affinity prediction 
(ranking)
Scoring function to discriminate correct docking complex structure from
incorrect ones
Strict control of false positives
No consensus (could be more than 1 result)
 
S
c
o
r
i
n
g
 
f
u
n
c
t
i
o
n
s
 
Scoring
 
functions
 
are
 
used
 
to
 
estimate
 
free energies of
binding
Force
-
field
 
scoring
 
(electrostatic + vdW (+ solvation) scoring)
GoldScore,
 
DOKC,
 
AutoDock
Empirical
 
scoring
 
(based on the conformation binding)
ChemScore,
 
Glide
 
SP/XP
Knowledge-­‐based
 
scoring
 (based on known protein-ligand
complex)
PMF,
 
DrugScore
Consensus
 
scoring
 
(combine result from rescoring experiment)
 
(
S
o
m
e
)
 
C
h
a
l
l
e
n
g
e
s
 
w
i
t
h
 
d
o
c
k
i
n
g
 
Docking method predicts 
the experimental pose about 70% 
of the time
Predicting the binding affinities of 
a diverse set of molecules 
is very
difficult
Scoring method is enormous
Search space is high dimensional; both molecules are very flexible
Scoring method is still imperfect-
> not 100% replicate the experimental
or too heavy in taking computational resource
About 
30 docking 
programs
 
D
o
c
k
i
n
g
 
P
a
c
k
a
g
e
s
 
Free
AutoDock
 
(Art Olsen, David Goodsell, Scripps)
UCSF DOCK (Kuntz Group)
Commercial
Glide (Schrodinger)
GOLD (CCDC)
FlexX(BiosolveIT)
ICM (Molsoft)
Surflex(Tripos)
Webserver
 (A LOT)
 
Session 12
 
Interaction Bioinformatics: Molecular
Docking
Section number : 5
Practice of Docking
 
Methods of Bioinformatics
 
W
h
a
t
 
y
o
u
 
n
e
e
d
 
t
o
 
d
o
 
a
 
d
o
c
k
i
n
g
 
Protein structure 
(for receptors or for protein-protein interaction)
Chemical compound structures 
(for ligands)
Molecular docking software
Visualizer software 
(if the docking software doesn’t have this)
 
G
o
o
d
 
d
o
c
k
i
n
g
 
t
a
r
g
e
t
?
 
Deep
, well-defined pocket
Shallow pockets have too many options
Sites
 for specific interactions
Many charge-charge or h-bonding sites
Mostly hydrophobic
;
 vdW
 
interactions bad
Well ordered 
side-chains
See 
Ramachandran Plot 
to see if your protein is good or not
 
R
e
c
e
p
t
o
r
 
p
r
e
p
a
r
a
t
i
o
n
 
Dependent
 on docking program used
 (some programs has its own set of
rules)
Structure 
and docking site 
selection
Add charges
 or 
add hydrogen
 atom
s
, some programs more sensitive to
positions than other
Remove/include 
waters, cofactors, metals
Pre-docking refinement
Remember to consider 
missing residues or atoms
 
(especially if getting
data from PDB file)
 
L
i
g
a
n
d
 
P
r
e
p
a
r
a
t
i
o
n
 
Input structures 
(extract from PDB, draw, convert from SMILES
 data
)
Add bond orders
Generate 
isomers
 if chiral
 
centers
Calculate charges
Predict pKa’s
 
for each potential charged atom
Generate a structure for each charge combination for a given pH range (e.g., 5-9)
Minimize structures
Generally using a molecular mechanics forcefield
For Screening
, download
 a
 public sets from ZINC (available compounds) or
PubChem
 
D
o
c
k
i
n
g
 
a
c
c
u
r
a
c
y
 
Accuracy measures
Generally, take average RMSD
 (root mean square deviation) 
comparing to crystal
structures
 or experimental data
Better analyses consider interactions
 (like what kind of interaction between the
protein residue and some part of the ligand)
In the end of the day, docking analysis is moot without any follow up as it
only predicts the interaction. 
Follow up could be Molecular dynamics or
wet lab analysis
 
 
 
 
 
O
t
h
e
r
 
w
a
y
:
 
R
E
D
O
C
K
!
 
You can use 
DECOY
 substances (other similar ligand but has different
properties, so it should NOT bind to your protein)
Redock with the natural ligand 
of the protein.
 
Session 12
 
Interaction Bioinformatics: Molecular
Docking
Section number : 6
Conclusion
 
Methods of Bioinformatics
 
C
o
n
c
l
u
s
i
o
n
 
Docking method is useful 
to determine the fitness 
of ligand-protein
binding in accordance with the thermodynamics law
Docking method could be helpful in 
drug and vaccine design
 
R
e
f
e
r
e
n
c
e
s
 
Dar AM, Mir S (2017) Molecular Docking: Approaches, Types,
Applications
 
and Basic Challenges. J Anal Bioanal Tech 8: 356. doi:
10.4172/2155-9872.1000356
Molecules 2015, 20, 13384-13421; doi:10.3390/molecules200713384
Meng et al. 
Molecular Docking: A powerful approach for structure-
based
 
drug discovery
. Curr Comput Aided Drug Des. 2011 June 1;
7(2): 146–157.
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Explore the world of molecular docking in bioinformatics through in silico approaches, learning about protein-ligand interactions, modes of docking, different docking approaches, and the theory of enzymes. Discover how this computational method helps predict the binding affinity and conformation of molecules, aiding in drug discovery and understanding molecular interactions.


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  1. Methods of Bioinformatics Session 12 Interaction Bioinformatics: Molecular Docking

  2. Related Learning Outcomes Related Learning Outcomes By the end of this session, students will be able to: To understand The docking analysis

  3. Outline Outline 1. Molecular Docking Definition 2. Theory of Enzyme 3. Thermodynamics and Docking 4. Tasks of Docking 5. Practice of Docking 6. Conclusion

  4. Methods of Bioinformatics Session 12 Interaction Bioinformatics: Molecular Docking Section number : 1 Molecular Docking Definition

  5. Molecular Docking

  6. What? What? In silico (computer-based) approach The approach is totally done in a computer. Yet the data is not always Identification of bound conformation Check how your chemicals bind to each other. In which part? How is the conformation? Prediction of binding affinity How strong the bond is? Docking vs. (Virtual) Screening Similar but not the same

  7. Protein-Ligand Docking Protein-Protein Docking

  8. Modes of Docking Modes of Docking 2 Modes : Respective: How does your molecule bind? What is its mode of action? What might be the reaction mechanism? Prospective: What compounds might be good leads? What compound(s) should you make?

  9. Docking approaches Docking approaches in a nutshell in a nutshell Fast, Simple Initially Receptor (protein) and ligand rigid Most current approaches Receptor rigid, ligand flexible Advanced approaches Receptor (to a degree) and ligand flexible Slow, Complex

  10. Methods of Bioinformatics Session 12 Interaction Bioinformatics: Molecular Docking Section number : 2 Theory of Enzyme

  11. Key Key- -lock Theory lock Theory Specific action of a protein with a single substrate (Postulated by Emil Fischer in 1894) Lock is enzyme, key is substrate Only the CORRECT SIZE and CONFORMATION key (substrate) will fit to The keyhole of the lock (enzyme)

  12. Induced Fit Theory Induced Fit Theory Not all experimental evidence can be adequately explained using the key- lock theory Assumes that the substrate plays a role in determining the final shape of the enzyme and that the enzyme is PARTIALLY FLEXIBLE. It explains some compound can bind but no reaction occurs; enzyme is distorted too much due to binding Others are too small to induce proper alignment Only the proper substrate can induce proper alignment to the active site

  13. Both theories underline the different types of docking Complexity on both receptor and ligand also play a pivotal role

  14. Methods of Bioinformatics Session 12 Interaction Bioinformatics: Molecular Docking Section number : 3 Thermodynamics and Docking

  15. Molecular Recognition Molecular Recognition The central phenomenon in biochemistry Enzyme with substrate Protein receptor and ligand Antigen and antibody Etc. How to investigate those? Molecular Docking Free energy calculations QM/MM (quantum mechanics/molecular mechanics) method OUR FOCUS TODAY

  16. Some definitions first Some definitions first pKd measures tightness of binding pKi measures ability to inhibit Gibbs free energy of binding: Mechanisms: Competitive inhibition (most typical in docking) Allosteric inhibition (inhibitors bind to different pocket to inhibit enzyme) Allosteric activation (activators bind to different pocket to activate enzyme)

  17. Energy binding?? Energy binding?? Molecular recognition based on enthalpy and entropy Enthalpy: Direct interactions between ligand, solvent, proteins, ions Ligand-protein Ligand-solvent Protein-solvent Conformational changes during binding

  18. Energy binding?? Energy binding?? Entropy: Rotational and translational entropy Conformational entropy Solvent reorganization (based on protein or ligand hydrophobicity) Vibrational entropy Don t worry, the software will calculate for you, you just need to know what is the energy meaning

  19. Methods of Bioinformatics Session 12 Interaction Bioinformatics: Molecular Docking Section number : 4 Task of Docking

  20. What What is is docking docking exactly? exactly? Finding the right pose of ligand and protein! Making difference between right and wrong docking poses Making difference between high and not so high affinity compounds

  21. 3 tasks of Molecular Docking 3 tasks of Molecular Docking

  22. Usage Usage Reproduce the binding mode of x- ray ligand Predicting the binding mode of a known active ligands Predicting the binding affinities of related compounds from a known active series Identifying new ligands using virtual screening

  23. Docking approaches Docking approaches Initially Receptor (protein) and ligand rigid Search the relative orientation of 2 molecules with the lowest energy Conformational analysis needed for both molecules Software: FLOG Most current approaches Receptor rigid, ligand flexible Need several protein structures Software: GOLD, Autodock, GLIDE Advanced approaches Receptor (to a degree) and ligand flexible Induced-fit method (GLIDE, MOE) Sidechain flexibility (Surf-flex, GOLD, Autodock)

  24. Docking workflow Docking workflow Binding mode prediction Search algorithm to find the docking complex structure by scoring function Consume lots of CPU-time Binding affinity prediction (ranking) Scoring function to discriminate correct docking complex structure from incorrect ones Strict control of false positives No consensus (could be more than 1 result)

  25. Scoring functions Scoring functions Scoring functions are used to estimate free energies of binding Force-field scoring (electrostatic + vdW (+ solvation) scoring) GoldScore, DOKC, AutoDock Empirical scoring (based on the conformation binding) ChemScore, Glide SP/XP Knowledge- based scoring (based on known protein-ligand complex) PMF, DrugScore Consensus scoring (combine result from rescoring experiment)

  26. (Some) Challenges with docking (Some) Challenges with docking Docking method predicts the experimental pose about 70% of the time Predicting the binding affinities of a diverse set of molecules is very difficult Scoring method is enormous Search space is high dimensional; both molecules are very flexible Scoring method is still imperfect-> not 100% replicate the experimental or too heavy in taking computational resource About 30 docking programs

  27. Docking Packages Docking Packages Free AutoDock (Art Olsen, David Goodsell, Scripps) UCSF DOCK (Kuntz Group) Commercial Glide (Schrodinger) GOLD (CCDC) FlexX(BiosolveIT) ICM (Molsoft) Surflex(Tripos) Webserver (A LOT)

  28. Methods of Bioinformatics Session 12 Interaction Bioinformatics: Molecular Docking Section number : 5 Practice of Docking

  29. What you need to do a docking What you need to do a docking Protein structure (for receptors or for protein-protein interaction) Chemical compound structures (for ligands) Molecular docking software Visualizer software (if the docking software doesn t have this)

  30. Good docking target? Good docking target? Deep, well-defined pocket Shallow pockets have too many options Sites for specific interactions Many charge-charge or h-bonding sites Mostly hydrophobic; vdW interactions bad Well ordered side-chains See Ramachandran Plot to see if your protein is good or not

  31. Receptor preparation Receptor preparation Dependent on docking program used (some programs has its own set of rules) Structure and docking site selection Add charges or add hydrogen atoms, some programs more sensitive to positions than other Remove/include waters, cofactors, metals Pre-docking refinement Remember to consider missing residues or atoms (especially if getting data from PDB file)

  32. Ligand Preparation Ligand Preparation Input structures (extract from PDB, draw, convert from SMILES data) Add bond orders Generate isomers if chiral centers Calculate charges Predict pKa s for each potential charged atom Generate a structure for each charge combination for a given pH range (e.g., 5-9) Minimize structures Generally using a molecular mechanics forcefield For Screening, download a public sets from ZINC (available compounds) or PubChem

  33. Docking accuracy Docking accuracy Accuracy measures Generally, take average RMSD (root mean square deviation) comparing to crystal structures or experimental data Better analyses consider interactions (like what kind of interaction between the protein residue and some part of the ligand) In the end of the day, docking analysis is moot without any follow up as it only predicts the interaction. Follow up could be Molecular dynamics or wet lab analysis

  34. Other way: REDOCK! Other way: REDOCK! You can use DECOY substances (other similar ligand but has different properties, so it should NOT bind to your protein) Redock with the natural ligand of the protein.

  35. Methods of Bioinformatics Session 12 Interaction Bioinformatics: Molecular Docking Section number : 6 Conclusion

  36. Conclusion Conclusion Docking method is useful to determine the fitness of ligand-protein binding in accordance with the thermodynamics law Docking method could be helpful in drug and vaccine design

  37. References References Dar AM, Mir S (2017) Molecular Docking: Approaches, Types, Applications and Basic Challenges. J Anal Bioanal Tech 8: 356. doi: 10.4172/2155-9872.1000356 Molecules 2015, 20, 13384-13421; doi:10.3390/molecules200713384 Meng et al. Molecular Docking: A powerful approach for structure- based drug discovery. Curr Comput Aided Drug Des. 2011 June 1; 7(2): 146 157.

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