Drug Discovery & Drug Design from Natural Resources

1. Natural Products in Drug Discovery
Dr. G. Sakthivel

2. What is Drug?
A chemical substances administered to the
person or animal to cure disease.
Webster’s Dictionary….
An agent intended diagnose, switch ON or OF
certain enzymatic action, treat cure or prevent
diseases in human or other animals.
Expanded definition….

3. What is?
Drug Discovery & Drug Design
Drug discovery includes:
• Concept
• Mechanism
• Serious biological assay
• Screening hit identification
• In-vivo proof of concept in animals and therapeutic index
Development begins when the decision is made to put
a molecule into Phase I clinical trials
Mandal et al., "Rational drug design."European journal of pharmacology 625.1 (2009): 90-100.

4. Drug design includes:
• Development of small molecules with desired properties for
targets, biomolecules (proteins or nucleic acids),
• whose functional roles in cellular processes and 3D structural
information are known.
• This approaching drug design is well established and
• Is being applied extensively by the pharmaceutical industries.
• Development of small molecules with predefined properties for
targets (whose cellular functions and their structural
information may be known or unknown.
• Knowledge of unknown targets (genes and proteins) can be
obtained by analyzing data bases using advanced
computational tools.
Mandal et al., "Rational drug design."European journal of pharmacology 625.1 (2009): 90-100.

5. Characteristics of Drugs:
• Molecular weight and size
• Structure-activity relationship
• Solubility
• Dosage form
• Should maintain the half life time
• It will not produce any toxicity or side effects
• Affinity to bind with target or plasma proteins or
receptors.
• Should not affect the other enzymatic or
physiological function.
epharmacology.hubpages.com/hub/Characteristics-of-Drug

6. Drug Discovery & Development Process
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Preclinical testing
(1-3 years)
Formulation
Human clinical trials
(2-10 years)
Scale-up
Approval
(2-3 years)

7. THE DISCOVERY PROCESS
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Pre-discovery
Target identification
Target validation
Lead identification & optimization
Preclinical testing
Development Process (Phase I, II &
II)

8. THE DISCOVERY PROCESS
Step 1 Pre-discovery
Understand the disease
• Before any potential new medicine can be
discovered, First work to understand the disease to
be treated as well as possible.
• They try to understand how the genes are altered.
• how that affects the proteins they encode and how
those proteins interact with each other in living
cells.
• How those affected cells change the specific tissue
they are in and finally how the disease affects the
entire patient.
• This knowledge is the basis for treating the
problem.

9. THE DISCOVERY PROCESS
Step 2 Target identification
Choose a molecule to target with a drug
• A target is generally a single molecule, such as a gene or
protein, which is involved in a particular disease.
• Even at this early stage in drug discovery it is critical that
researchers pick a target that is “drug able”
• i.e., one that can potentially interact with and be affected by a
drug molecule.
DNA, Protein or Enzyme

11. THE DISCOVERY PROCESS
Step 3 Target validation
Test the target and confirm its role in the disease
• Demon-strate that a particular target is relevant to the
disease being studied through complicated experiments in
both living cells and in animal models of disease .

12. THE DISCOVERY PROCESS
Step 4 Lead identification & optimization
There are a few ways to find a lead compound
Mother Nature:
• Until recently, scientists usually turned to nature to find
interesting compounds for fighting disease.

13. sources
Microbial
World
Animal
Sources
Marine
World
Venom
&
Toxins
Plant
Kingdom

14. THE DISCOVERY PROCESS
Step 4 Lead identification & optimization
There are a few ways to find a lead compound
Mother Nature:
• Until recently, scientists usually turned to nature to find
interesting compounds for fighting disease.
Mother nature still offers many useful substances, but now there
are other ways to approach drug discovery .
• De novo
• High-throughput Screening

15. THE DISCOVERY PROCESS
Lead optimization
• Lead compounds go through a series of tests to provide an early
assessment of the safety of the lead compound.
• Test include Absorption
• Distribution
• Metabolism
• Excretion and Toxicological (ADME/Tox) properties.
Step 4 Lead identification & optimization
Early Safety Tests:

16. Venom & Toxin Based Drug Discovery Approach
Basic Work Flow
• Characterization of venom:
MALDI-TOF Mass spectrometry
• Isolate and purification of toxin peptides from venom
Gel electrophoresis and Chromatography techniques like reverse-phase HPLC
• Sequencing and structure determination of isolated peptides.
Liquid phase sequencer and Automated sequencing method. Mass Spectrometry,
NMR and X-ray Crystallography for structure predication.
• Invivo and Invitro study for the activity of isolated major peptides.
Explore the pharmacological and systematic function of the toxin.
• Computational & system biology approach
Computational biological & system approach will be implemented to calculate the
accurate binding pathway and target the structural function of the peptides with the
target membrane receptors

17. THE DISCOVERY PROCESS
Step 5 Preclinical testing
• Lab and animal testing to determine if the drug is safe
enough for human testing

18. Important Points in Drug Design based on
Bioinformatics Tools
• Chemical Modification of Known Drugs
– Drug improvement by chemical modification
– Pencillin G -> Methicillin; morphine->nalorphine
• Receptor Based drug design
– Receptor is the target (usually a protein)
– Drug molecule binds to cause biological effects
– It is also called lock and key system
– Structure determination of receptor is important
• Ligand-based drug design
– Search a lead compound or active ligand
– Structure of ligand guide the drug design process

19. 3D Visualization
• X-ray crystallography and NMR Spectroscopy can
reveal 3D structure of protein and bound
compounds
• Visualization of these “complexes” of proteins and
potential drugs can help scientists understand the
mechanism of action of the drug and to improve
the design of a drug
• Visualization uses computational “ball and stick”
model of atoms and bonds, as well as surfaces
• Stereoscopic visualization available

20. Binding Site Identification
• Before beginning molecular interaction
calculations…
• Where is the active site? ?

21. Molecular Interaction concept

22. Overview Continued –
A simple example
Protein
Small molecule
drug
Protein
Function Switch ON or OF

23. The Crystal Structure Determination of a Protein (PDB:1DPY)

24. The Crystal Structure Determination of a Protein (PDB:1DPY)

25. Active Site region (PDB:1DPY)
ASP 49
&
HIS48

26. High-Throughput Screening
• Drug companies now have millions of samples of
chemical compounds.
• High-throughput screening can test 100,000
compounds a day for activity against a protein target.
• Maybe tens of thousands of these compounds will
show some activity for the protein.
• The chemist needs to intelligently select the 2 - 3
classes of compounds that show the most promise for
being drugs to follow-up.
?

27. High-Throughput Screening

29. MOLECULAR DOCKING & PHARMACOPHORE IDENTIFICATION

30. Molecular Modeling
3D Visualization of interactions between
compounds and proteins

31. Template(s)
selection
Sequence
Alignment
Structure
Modeling
StructureEvaluation
Final Structural
Models
Target
sequence
Sequence retriew from NCBI Database
Known
Structures
(templates)
STEPS
PHYRES online template search tool
http://www.sbg.bio.ic.ac.uk/phyre
Sequence Similarity / Fold
recognition. Structure quality
(resolution, experimental
method)Experimental
conditions
Template model & satisfaction of Spatial
Restraints: MODELLER
Structure properties & function study
Pharmacophore Identification

33. In Silico ADME Models
• Computational methods can predict compound
properties important to ADME, e.g.
– LogP, a liphophilicity measure
– Solubility
– Permeability
– Cytochrome p450 metabolism
• Means estimates can be made for millions of compounds,
helping reduce “attrition” – the failure rate of compounds
in late stage

34. Major Molecular Interaction or Docking Software's
Accelrys discovery studio (commercial)
Schrödinger Suit (one year student licence)
AutoDock Tool (Academic version free)
Other:
• Gold
• ICM-PRO

35. Directory of computer-aided Drug Design tools

36. Thank You