drug design and molecular docking

2. Molecular Docking
• S. Shahriar Arab

3. Presented by
VIVEK K
RAHUL BS

4. Drug discovery
Take years to decade for discovering a new drug and
very costly
 To cut down the research timeline and cost by
reducing wet-lab experiment
use computer modeling
softwares
Drugs interact with their receptors in a highly specific
and complementary manner.
Core of the (target-based) structure-based drug design
(SBDD) is lead generation and optimization

5.  Pharmacophore- the atoms and functional groups required
for a specific pharmacological activity, and their relative
position in space.
 3D arrangement of functional groups that enable a
compound to exert a particular biological effect.

7. In silico design
In-silico design
Receptor
based
Denovo
based
In silico Ligand
design based
Combinatorial

8. Receptor/structure based approach
Active site identification
No
Complex growing
Ligand fragments grouping
yes
Fit for receptor
No
yes
Potential drug
Change receptor

9. Ligand based approach
Pharmacophore identification
Pharmacophore modification
No
Fit to receptor
Yes
Potential drug

10. Combinatorial based approach
•
Automated
or
semiautomated
process
of
synthesising large quantity of compounds in small
scale
Denovo based approach
•
Purely based on molecular modelling study of binding
site.
•
Searching large data bases to identify proper ligand.

11. Different terms used in in-silico design
 Receptor/Host/Lock – receiving molecule (protein) – large.
 Ligand/ Guest/ Key – molecule bind to receptor –small.
 Docking – Computational simulation of a candidate – preffered
orientation of ligand binding site to a receptor.
 Binding mode – conformation of ligand-receptor bound to each
other.
 Pose – a candidate binding mode.
 Scoring – evaluating a particular pose by counting the number
of favourable intermolecular interactions.

12.  Ranking – classify ligands most likely to interact
favourably to a particular relation based on ∆G of binding.
 Hit – Ligand with high rank.
 Lead – hit with biological activity.
 Pharmacophore – spacial arrangement of atoms or groups
believed to be responsible for biological activity.
 Rational drug design – Modulation of specific biological
target may have therapeutic value.
 QSAR – Study of physico chemical properties of a
compound with its biological/pharmacological activity.
 Drug design – design of ligands.

13. Docking
Docking attempts to find the “best” matching
between two molecules

14. ....a more serious definition….
Docking is a method which predicts the preffered
orientation of one molecule to a second when bound to form a
stable complex with overall minimum energy.
•
Docking is used to predict both strength & type of signal produced.

15. •
Aim of molecular docking is to achieve an optimized
conformation & relative orientation between protein ligand such
that ∆G is minimized.
It is to study. . . . .
 Whether the two molecules interact with each other
 If
so what is the orientation that maximizes the
interaction which minimizing the total energy of the
complex
Goal. . .
Given a protein structure and predict its ligand bindings.

16. Why is docking important?
It is of extreme relevance in cellular biology
It is the key to rational drug design

17. Docking approaches
i.
Uses a matching technique – describes the protein
and ligand as complementary surfaces.
ii. Simulates the actual docking process in which ligandprotein pairwise interaction energies are calculated

18. a) Shape complementarity

Receptor’s molecular surface – solvent accessible surface
area.

Ligand’s molecular surface – matching surface description.
Advantage
 Fast & robust
Disadvantage
 Can't model the dynamic changes in the ligand / protein
conformations accurately.

19. b) Simulation
 Protein and ligands are separated by a physical distance
 Binding takes place only after certain moves
(translations, rotations,& internal changes like torsional
angle rotations) in its conformational space.
 In every move total energy of the system is calculated.
Disadvantage
 It take longer time for evaluation (overcome by using grid
based technique & fast optimization methods)

20. Factors affecting docking
Intramolecular forces. . . .
bond length
bond angle
dihedral angle
Intermolecular forces. . . .
electrostatic
dipolar
H-bonding
hydrophobicity
Vander waals forces

21. Different type of interactions
Interactions between particles can be defined as a
consequence of forces between molecules connected by
particles.
Drug + receptor
Kf
Kr
Complex
Kf – rate constant for association of the complex
Kr – rate constant of dissociation of the complex
Affinity, Kas = Kf / Kr
Biological activity of a drug is related to its affinity Kas
for the receptor

22. Electrostatic energy
 Involves integration of overall electron clouds of the
two molecule.
 Longest range.
Ion-ion
(1/R)
Dipoledipole
Iondipole
(1/R3)
(1/R2)

23. Electrodynamic forces
 Attractive forces existing between all pairs of atoms,even
between rare gas atoms.
 Depends on polarizability & number of valence electrons
of interacting molecule.
 Polarization energy involves the interaction of a molecule
that is already polar with another polar/non polar
molecule.
 Eg. London or Vander waals forces.

24. Steric forces
 Each atom wthin the molecule occupies a certain amount of
space.
 If atoms are too closer there is an associated lost in
energy due to overlapping electron cloud – may affect
molecules preferred shape, reactivity and activation
energies of most chemical reaction.
 Steric effect will determine how & at what rate a drug will
interact with its target biomolecule.

25. Solvent related forces
 these are forces generated due to chemical reaction
between the solvent & protein or ligand.
Eg. Hydrogen bonds (hydrophyllic interactions)
Hydrophobic interactions

26. Mechanics of docking
Methods to derive 3D structures

27. X – ray crystallography
Protein + precipitating medium
individual protein
molecule
data collection using
Computer controlled
detector
phase & amplitude of diffracted
waves calculated & combined with
experimentally observed structural
functions
Protein structure
arrange to form a
crystalline entity (single crystalline x ray
diffraction)
image of electron
diffracting cloud
(electron density map)
model building & refinement
(electron density fitting program
FRODO, TNT)

28. Proton detected heteronuclear NMR
Protein + drug
spectrum re run
Drug fail to combine
with protein
NMR still be
detected
drug bind to
protein
nuclei will have shorter
relaxation time
no NMR spectrum

29. Homologous modelling
 Align the amino acid sequence of protein with unknown
structural agent, the sequence of a homologous protein
whose 3D structure has already been determined.
 By converting structurally conserved region & structural
variable region, the core of the molecule can be identified.

30. Prepared
protein
structure
Input to
docking
program
Database
of potential
ligands
Search
algorithm
Scoring
function
Success of
docking
program

31. a) Search algorithm
 Determine all possible optimal conformation for a given
complex (protein-ligand/ protein-protein)
 Calculate the energy of resulting complex & of each
individual interactions.
Conformational search strategies include
• Systematic/ stochastic torsional searches about rotatable
bonds.
• Molecular dynamic simulations
• Genetic algorithms to evolve new low energy conformations

32. Ligand flexibility
 Conformation of the ligand may be generated in the
absence of receptor or in the presence of receptor
binding activity.
Force field
energy
evaluation
Knowledge based
method
Receptor flexibility
 Large number of degrees of freedom
experimentally
determined
multiple steric
structures
Rotamer libraries
of aminoacid side
chain surrounds
the binding cavity

33. b) Scoring function

34. Types of docking
a) Lock and key/ rigid docking
b) b) Induced fitting/ flexible docking

35. MOLECULAR DOCKING
• Docking- the process by which molecular modeling
software fits a molecule into target binding sites.
• Used for finding binding modes of protein with
ligands/inhibitors
• In molecular docking, attempt to predict the structure of
the intermolecular complex formed between two or more
molecules

36. MANUAL DOCKING
Dock or fit a
molecule in the
binding site
Binding group on the
ligand and binding site
are known, defined by
the operator.
Ideal bonding
distance for
potential
interaction is
defined.
Binding group in the ligand is
paired with its
complementary group in the
binding site
Docking
procedure is
started
The program try to get
best fit, as defined by
the operator

37. The paired groups are not
directly overlaid, they are
fitted within preferred
bonding distance.
Both ligand and protein
remain same
conformation throughout
the process
Same as in energy
minimization.
So this is a rigid fit, once a
molecule successfully
docked fit optimization is
carried out.
Different conformation
of molecule can be
docked to in same way
Identify the best fit

38. FLEXIBLE DOCKING
Rigid docking- the protein and the ligand as rigid bodies.
The
drawback
of
rigid
docking
is,
since
it neglects the conformational degrees of freedom of
ligands.
It fails to give satisfactory answer for flexible ligand, will
form different conformations.

39. To solve this, dock different conformations of ligand as
possible in order to get the best result.
FLOG (flexible ligand oriented on grid) is a program that
generates conformational libraries called flexibose, contain
10-20 conformations for each ligand studied.

40. DOCKING OF FLEXIBLE LIGANDS
Various programs
are for generate
different ligand
conformations
The popular
method is to
fragment the
ligand , identify a
rigid anchor
fragment which
can be docked
Examples of programs
Then reconstruct
or grow the
molecule back
onto the anchor.

41. Direct dock and dock 4.0
The algorithm
identifies the
rotatable bonds
present In the
ligand
Identification of
flexible and rigid
region
Molecule is
split into
fragments

42. The most rigid
fragment is termed
as anchor
Torison angle is
varied for each
addition
This increases the
partially build
structures(contructs)
Docked by shape
complimentarity
Flexible parts then
added sequentially
to the anchor.
Selection of limited
number constructs
based on binding and
difference in their
structures

43. The segments are added in
layers working outwards
The segments in the layer 1
are added sequentially before
the segments in layer 2 .
FLEX
The software also uses the anchor and grow method
The anchor is docked according to chemical
complementarity.

44. Docking is determined by the intermolecular interactions
formed between the anchor and binding site.
Docking the anchor by chemical complementarity rather
than steric complementarity has the advantage to cut down
the number of possible binding orientation for the anchor.
An interaction surface consisting interaction points

46. Matching process occurs, it matches atoms on
the anchor to interaction points in the binding
sites
The distance between atoms on the anchor
must match the distance between interaction
points in the binding site
The anchor atom and corresponding interaction
point must have binding compatibility
Docking requires identification of 3 matched pairs of
anchor atoms, equal to identifying complimentary
pharmacophore triangles for the anchor & binding site

47. Matching process -Comparison of
pharmacophore triangles for the ligand
and binding site
For a match a triangle for the ligand have
same dimensions as a triangle for the
binding site, but also the corners of the
triangle must have binding compatibility
The docking is now carried out such that
anchor atoms are overlaid with their
matched interaction point in the binding
site.

48. The procedure ensures that the angle requirements for hydrogen
bonding are fine with respect to the interaction points in the
binding site .

49. Problems
The anchor has to be chosen manually, becomes
difficult when large number of structures
Vast number of different pharmacophore triangles
constructed to represent the binding site.

50. HAMMERHEAD PROGRAM
Anchor and grow program
Probes are placed into the binding site in order to identify
locations of binding interactions
The probes used are hydrogen atoms as well as c=o and NH
fragments

51. Each probes can be scored as high scoring or low scoring
based on No. of hydrogen bonds it can form.
Once the probe has positioned, they act as the targets for
docking procedure.

52. Matching of atoms of a molecular fragment with probes,
docking must involve at least one of the high scoring probes.
Both steric and chemical complementarity is used in the
matching process.
Once the match has been identified the docking operation is
carried out.
Since the ligand is split into fragments, have limited
number of rotatable bonds

53. All fragments that are formed contain an atom or bond that is
shared with another fragment.
For each fragment, a number of conformations are
generated.

54. The fragments are docked and scored
Fragments that are particularly high scoring are defined as
head and act as an anchors
The remaining fragments are defined as tails
The reconstruction phase is carried out for each fragment
that has been identified as potential anchor.

55. The tails are then docked
The first fragments share an atom or bond with the anchor
and is docked like that it is aligned both to the relevant atom
or bond on the anchor.
Two fragments are then merged by overlaying the shared
bonds or atoms.
The tail fragments moves to the anchor

57. Advantages
Anchors are chosen automatically
Different anchors possible and investigated

58. Docking Of Flexible Ligands, By Simulated
Annealing And Genetic Algorithm
 This method is viable for docking of the flexible ligands.
 It involves use of metropolis method by using montecarlo
algorithms for conformational analysis.
 The ligand is placed randomly in the space close to the
binding site.

59.  Montecarlo algorithms are used to generate different
conformations
 The molecules are translated and rotated such that it
tumbles within the binding site.
 Different conformations are generated at different
position and orientation with in the binding site.
 Binding energy of each structure is measured as it is
formed and compared with the previous structure.

60. Docking Programs Using Monte Carlo
Algorithms For Docking
 Auto dock
 Mcdock
 Prodock and pro-lead.
Disadvantage
The quality of result is often depends on how the initial
structure s placed in the binding site.
This can be over come by using combination of programs
Eg; DOCK and Montecarlo based programs

61. Docking programs
Docking programs
DOCK (I. D. Kuntz, UCSF)
AutoDock (Arthur Olson, The Scripps Research Institute)
AutoDock was designed to dock flexible ligands into
receptor binding sites
The strongest feature of AutoDock is the range of
powerful optimization algorithms available
RosettaDOCK (Baker, Washington Univ., Gray, Johns
Hopkins Univ.)

62. Overall steps in docking
1) Get the complex from P.D.B
2) Clean the complex
3) Add the missing hydrogens/side chain atoms & minimized
the complex
4) Clean the minimized complex
5) Separate the minimized complex in macromolecule (lock)
& ligand (key)
6) Prepare the docking suitable files for lock & key
7) Prepare all the needing files for docking
8) Run the docking
9) Analyze the docking results

63. Working methodology of Schrodinger
i.




ii.

Protein preparation (protein preparation wizard)
Prepare co crystallized ligands – correctly define
multiple bonds & adding hydrogen
Neutralize residues that do not participate in the salt
bridge
Preprocess the receptor before grid generation
Optimization of the protein
Ligand preparation (ligprep)
Generate energy minimized 3D structures –
tautomeric, stereochemical and ionization variations as
well as energy
minimizations

64. iii. Docking
 Generate receptor grid around the site using glide
 Docking conducted using XP GLIDE (Extra precision)
iv. Visual inspection
 Images were obtained using Glide XP Vsualiser panel

65. Applications
 Hit identification
 Lead optimization
 Bio remediation
 virtual screening of large databases

66. References
i. Introduction to molecular docking; Edelmiromomen;
Pharmaceutical & Medicinal chemistry; Saarland
university.
ii. Protein-ligand docking methods; Thomas Funkhouser;Princeton
university
iii.Introduction to molecular docking; Carlos. P.Sosa; university of Minnesofa
iv. Molecular docking tutorial; Khuled.H.Brakat; Pharma matrix work
shopin, Computational biophysics.
v. Principles of Docking: An overview of search Algorithm & a guide to scoring functions;
Inbal Halperin,Buyon Ma.
vi. An introduction to medicinal chemistry; 4th edition; Graham.L.Patrick; Pg no. 352-361
vii. The organic chemistry of drug design & drug action. 2nd edition; Richard.B.Silverman

68. All informations in this presentation is collected
from various sources available on internet and text
books….
This presentation is only for educational purpose….
we sincerely saying thanks to all