Molecular docking - Principles of drug discovery

1. MOLECULAR DOCKING
PRINCIPLES OF DRUG DISCOVERY
PRESENTED BY
LAXMAN I. NIMBALE
M. Pharmacy
Pharmacology Dept.
1

2. CONTENT:
•Definition
•Types
•Docking based screening
•De Novo drug design

3. DEFINITION
• DOCKING:
Docking is a structure based technique which attempts
to find the “best” match, between two molecules.
Docking is a molecular modeling technique that is
used to predict how a protein (enzyme) interacts with
small molecules (ligands).
Molecular docking can be defined as the binding of
small molecule called ligand, on to a specific site in a
larger molecule.
Docking is the computational determination of binding
affinity between molecules (protein structure and ligand).

4. Docking is a method which predicts the preferred orientation of one molecule to a
second when bound to each other to form a stable complex.

5. IMPORTANCE:
• It is the key to rational drug design
• Identification of the ligand’s correct binding geometry ( pose- a
candidate binding mode) in the binding site.
• The results of docking can be used to find inhibitors for specific target
proteins and thus to design new drugs.
• Signal transduction

6. Types of Docking
• Rigid docking
• Flexible docking
• Manual docking

7. Rigid Docking:
In the rigid docking molecules are rigid, in 3D space of one of the
molecule which brings into an optimal fit with the other molecules in
terms of a scoring function.

8. TARGET
MOLECULE
LIGAND
JIGSAW
PUZZLE

9. Flexible Docking:
• In flexible docking the molecules are flexible, confirmations of the
receptor and ligand molecules, as they appear in complex.
• In flexible docking the ligand is flexible and the receptor is rigid.
• Interaction produces conformational changes in ligand.

10. Manual Docking:
The user manually moves, rotates or translates the compound inside the
protein cavity, a new association energy is recorded, etc.

13. • Advantages:
- Quick
- Can be very efficient if the user knows well the interacting site
•Disadvantages:
-User dependent
-Obtain stupid results

14. Docking Based Screening
• Virtual based screening
• Molecular based screening

15. •Virtual basedscreening:
• The process of drug discovery has been re-organize with the
development of genomics, proteomics, bioinformatics and efficient
technologies like combinatorial chemistry, high throughput screening,
virtual screening, de novo design, in vitro, in silico screening and
structure based drug design.
• Virtual screen has emerged as a reliable, cost-effective and time saving
technique for the discovery of lead compound.

16. • The virtual screening approach for docking small molecules into a known
protein structure is a powerful tool for drug design that has become an
integral part of the drug discovery process in recent years.
• Based molecule modeling and computational analysis of chemical data
those compounds should be identified that are relevant for certain
biological receptor.
• Any virtual screening method faces two critical issues;
a) + docking, that is how the virtual ligand interacts with the receptor.
b) + scoring, that is how the quality of the designed structure is
estimated.

18. Main Steps:
• Identify and determine the structure of the receptor
• Suggest a set of potential ligands that bound the receptor based on
theoretical principles and experimental data.
• Determine the structure of the receptor-ligand that leads to successful
bound with a minimum energy levels.
• Repeat step (2) and (3) in order to improve the receptor-ligand
interaction.

19. •Molecular based screening:
• In molecular docking, attempt to predict the structure of the
intermolecular complex formed between two or more molecules.
• It is used for finding binding modes of protein with the ligands or
inhibitors.
• It has become an increasingly important tool for drug discovery.

20. • STEPS OF MOLECULARDOCKING:
The molecular docking involves the three steps as they;
a) Definitions of the structure of the target molecules
b) Location of the binding site
c) Determination of the binding mode

22. DE NOVO DRUG DESIGN:
Approaches:
• De novo design is the approach to build a customized ligand for a given
receptor.
• This approach involves the ligand optimization.
• Ligand optimization can be done by analyzing protein active site
properties that could be probable area of contact by the ligand.
• The analyzed active site properties are described to negative image of
protein such as hydrogen bond, hydrogen bond acceptor and hydrophobic
contact region.

24. • De novo means start a fresh, from the beginning, from the scratch.
• It is a process in which the 3D structure of receptor is used to design
newer molecules
• It involves the structural determination of the lead target complex and
lead modificaions using molecular modelling tools.
• Information available about target receptor but no existing leads that
can interact.

25. PRINCIPLES OF DE NOVO DRUG DESIGN
• Assembling possible compounds and evaluating their quality.
• Searching the sample space for novel structures with drug like
properties.
• In De novo design, the structure of the target should be known to a
high resolution, and the binding to site must be well defined.
• This should defines not only a shape constraint but hypothetical
interaction site, typically consisting of hydrogen bonds, electrostatic
and other non-covalent interactions.

26. • These can greatly reducing the sample space, as hydrogen bonds and
other anisotropic interactions can define specific orientations.

27. •Classification:
DE NOVO
LIGAND DESIGN
Active site
analysis method
Whole
molecules
method
Fragment based

28. •Active site analysis method:
•Methods for analysis of the active site do not construct
ligands rather they analyze the properties of the active
site, and usually determine favorable binding locations
for individual atoms or small fragments

29. •Advantages:
A small number of well placed fragments
e.g. lipophilic and hydrogen bonding can provide significant binding
energy.
Must be done to convert the fragment locations into a complete ligand.

30. •Whole molecules method:
• The whole molecules techniques fit ligands into a receptor active site, using
either shape complementarity alone or coupled with electrostatic fitting.
• Advantages:
• Known or synthesizable compound are generally studied by these methods
• Any hit produced may readily be tested for activity
• Disadvantages:
• Time consuming
• Main disadvantage is that of rigid body, whole fitting is likely to miss many good
candidates.

31. •Fragment based:
• This approach relies on the concept that a small number of well placed
fragments, each making favorable interactions with the enzyme is
capable of providing a significant overall binding energy.

32. •APPLICATIONS:
Design of HIV I protease inhibitors
Design of bradykinin receptor antagonist
Estrogen receptor antagonist
Purine nucleoside phosphorylase inhibitors

33. THANK YOU…