DRUG DISCOVERYBY DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER

1. http://newdrugapprovals.wordpress.com/

2.  http://newdrugapprovals.wordpress.com/
 http://www.allfordrugs.com/
 http://worlddrugtracker.blogspot.in/
 http://drug-scaleup-and-
manufacturing.webnode.com/
 http://amcrasto.wordpress.com/
 is the link to my blogs which tracks drugs worldwide
 US, CANADA, JAPAN, EU, CHINA , INDIA ETC

3. He was only in first standard in school
(Dec 2007) when I was Paralysed head to toe.
His smiling face sees me through day in and day out.
Vast readership from academia and industry motivates me, and keeps
me going.
Helping millions with free advertisement free websites and has million
hits on google
Thanks for helping me to keep lionel smiling

4.  Your own will power and determination will
reach you to the shore even if you are
drowned in the middle of a storm

5. Drug discovery
Formulation
Preclinical studies
Clinical trails
Any drug development process must proceed through several stages
in order to produce a product that is safe, efficacious, and has
passed
all regulatory requirements.

6. Target
Right molecule
Candidate drug
Preclinical
documentatio
n
Clinical
documentation
Drug Development
7 years
Drug Discovery
5-7 years

8. ProductsDrugsTargets & Leads
Target
selection
Target
to
Lead
Lead
to
candid
ate
Candidate
selection
to FTIH
FTIH to
PoC
PoC to
Commit
to Phase III
Phase
III
File &
Launch
Lifecycl
e mgt
9 - 16 y
12-24m 12-24m 30-33m 8-12m 12-44m 0-30m 18-66m 10-13m
Costs ~ $1 billion per
successful product

9. Compound
production
Manufacturing 0.5-2 years
Preclinical
Clinical
FDA/EMEA review
Drug Discovery Drug Development Registration
Launch
PhI PhII PhIII PhIV
CD(Candidate Drug) NDA(New Drug Application)

10. PhI PhII PhIII
Drug Discovery Drug Development
RegistrationPreclinical
• GLP (Good Laboratory Practice)
• GCP (Good Clinical Practice)
• GMP(Good Manufacturing
Practice)
NDA
New Drug Application
IND
Investigational New Drug
(first time in man)
Preclinical

11. PhI PhII PhIII
Drug Discovery Drug Development
RegistrationPreclinical
Patents:
•Structure class
•Compound specific
•Synthesis
•Indication
•Formulation
•....
Patent time:
•20 years from the filing date
•Drug development 10-14 years

14. chemical
diversity
(compound
library)
test safety&efficacy
in animals and
humans
gene screen and
identify lead
Lead
optimisation
protein
target
DrugsTargets & Leads
Target Validation & Selection Target to Lead
(compounds)
Lead to
candidate
Drugs
Candidate progress
to FTIH and PoC in
patients

15. Target :Naturally existing cellular or molecular structure
involved in the disease pathology on which the drug acts
Targets
Types
Target validation :Involves demonstrating that a molecular
target
is critically involved in a disease process & modulation of the
target is likely to have a therapeutic effect
•Subject of discovery which include proteins
whose is discovered by function basic
scientific research
New
•Have a detailed description of its functions
in normal pathology involved in human
Established

16. Genome Disease
Potential Drug Target
Select protein of interest Pathology
Link with disease or
disease process
Selection of Biological
Target
Genetics
Target Selection
Approaches to Finding
a Drug Target

17.  Screening :Investigation of a great number of compounds for a
particular problem or feature of them
Random
 Screening Non-random
Cross
 Random involves no intellectualization & assays are done with out
structural regards
 Non-random also known as targeted or focused & more narrow
approach. compounds having a vague resemblance to weakly
active compounds uncovered in a random screened
 Whether the "hits" against the chosen target will interfere with
other related targets - this is the process of cross-screening

18.  Types of screens
◦ Functional assay
◦ Binding assay
Cell
response
Compound binds to cell surface
receptor - this can be measured
in a “binding assay”
This can evoke a cellular
response - which can be
measured in a “functional
assay”

19.  Nature of sources
 Chemical sources
 Rational approches
 Molecular modelling
 Combnitorial chemistry
 Biotechnology
 Bioinformatics
 Preclinical studies
 Clinicaltrails

20. Plant species provide a potenial source of strating or crude
material for the drug discovery
Many cardiotonics are plant derived
 Microbes are the main source of antimicrobial drugs
 Streptomyces species have been a source of antibiotics.
 Marine environments are potential sources for new
bioactive agents.
Arabinose neucleosides discovered from marine
invertebates
Plant
derivatives
Marine
invertebrates
Microbial
metabolites

21.  Ligand based
◦ Knowledge of other molecules
that bind to the target
◦ Build on known pharmacophore
 Structure based
◦ Knowledge of three dimensional
structure of the target (X-ray or
NMR)
◦ Docking

22.  In vitro
◦ Functional cell-based assays (FLIPR)
 Intracellular calcium mobilization (GCRP)
 In vivo Species differences!
◦ Potency in vivo?
 Agonist induced models ( NK1 and NK2)
◦ Effective in IBS?
 Disease related models

23. Permeability Metabolism

24.  Organic Chemistry involved in Synthesis & Purification
 Organic chemists synthesize new drug compounds as well as
isolate and characterize natural products, such as alkaloids. In
each case, there is interest in the complex relationships between
chemical structure and pharmacological action.
 The pharmacological activity of a compound is an involved
function of the structure, and very small changes may pro-
foundly modify the pharmacological effect.
 These structural modifications may involve replacing one group
with another at a specific point in the molecule, shifting the
same group from place to place in the parent
molecule, saturating valence bonds or modifying the acidity or
basicity.
 Total synthesis is made possible by knowledge of chemical
structures and, in many instances, is important economically in
reducing the cost of the drug.1 Chromatographic techniques
have been widely used for the purification of newly synthesized
compounds.

25.  The first step in product characterization is to establish
the precise chemical identity of the product. It is important
to determine whether the material is a compound, i.e. a
single chemical entity, a mixture of closely related
compounds, mixture of isomers, or merely a loose
molecular complex of readily dissociable components.
Such information is fundamental to a proper evaluation of
the biological properties of the material.
For compounds of synthetic origin, identity is usually
clearly defined in the great majority of cases by the
synthetic route employed. However, it is essential not only
that identity be confirmed by alternative means but that
the means employed should be capable of providing rapid
verification whenever this may be required at any stage of
the development program. Modern spectroscopic
techniques, such as as1H and 13C NMR and infrared
spectroscopy are sensitive tools for such purposes.

26.  Once a new pharmaceutical lead compound has
been discovered, extensive and costly efforts
usually are made to prepare a series of analogues
in the hope that even better activity will be
found. In an effort to improve the efficiency of
analogue development, a variety of statistical
methods have been introduced.
 They range from the Hansch approach, in which
analysis of variance is used to derive an equation
expressing the quantitative relationships
between functional group changes and biologic
activity, to pattern recognition and factor analysis
methods

27.  Non-clinical risk and benefit assessment for
◦ estimation of an initital safe starting dose in human
◦ to support the clinical program
 Studies
◦ Pharmacodynamics
◦ Pharmacokinetics
◦ Toxicology
 Regulatory guidelines
 Quality requirements
Phase I Phase II Phase IIII Registration

28.  Rat and mouse
 2 years dosing
 Expensive
 Critical timeline
Phase I Phase II Phase IIII

29. Topics
 Lead optimisation – addition of
extra properties (ADME)
Safety testing
Molecules into Medicines
Testing in Humans

30. Medicinal
Chemistry
Biolog
y
Lead compounds from Screening
Candidate selected for testing in man
Developability
DMPK
Hypothesise,
design molecules
and synthesise
Analyse/
rationalise
results
Test
hypothesis

31. Chemical source
 These include semisynthetic drugs
 It has organic and inorganic sources
 Mineral resources are one of it.
 New source of chemical synthesis is Combinatorial
Chemistry
Combinatorial chemistry: involves the synthesis or
biosynthesis of chemical libraries (a family of compounds
having a certain base chemical structure) of molecules with
in a short period of time for the purpose of biological
screening, particularly for lead discovery or lead
modification.

32.  There different types of combinatorial synthesis
 combinatorial synthesis
 Split Synthesis: Peptide Libraries
 Encoding Combinatorial Libraries
 Nonpeptide Libraries
 The main differences among the various combinatorial
approaches are the solid support used, the methods for
assembling the building blocks, the state (immobilized or in
solution) and numbers (a fraction of the total library or
individual entities)

33. Hit -Lead:
Hit
confirmation
• Re-testing, dose response
curve,secondaary
screening,chemical
amnebilty,biophysical
techs &hit ranking and
clustering
Hit expansion
• Affinity, molecular weight
and lipophilicity can be
linked in single parameter
such as ligand efficiency
and lipophilic efficiency to
assess drug likness
Lead
optimization
• This optimization is
accomplished through
chemical modification of
the hit structure, with
modifications chosen by
employing SAR as well
as structure-based design

34. ssssTarget Identification
Genetics
Molecular Biology
Bioinformatics
Structure
Determination
X-ray Crystallography
NMR Spectroscopy
Computer-Aided Design
Molecular Modeling
Computer Graphics
Biological Assays
High-Throughput Screening
Computer-Based Screening
Synthetic Chemistry
Peptidomimetics
Combinatorial
Chemistry
Pre-clinical
Trials

35.  Acute Studies :The goal is to determine toxic dose levels and
observe clinical indications of toxicity.
 Data from acute toxic studies helps determine doses for repeated dose
studies in animals and Phase I studies in humans.
 Repeated Dose Studies :These are repeated dose studies may be
referred to as sub acute, sub chronic, or chronic. The specific duration
should anticipate the length of the clinical trial that will be conducted
on the new drug. Again, two species are typically required.
 Genetic Toxicity Studies :These studies assess the likelihood that the
drug compound is mutagenic or carcinogenic.

36.  Reproductive Toxicity Studies : Segment I reproductive toxic
studies look at the effects of the drug on fertility. Segment II and III
studies detect effects on embryonic and post-natal development
 Carcinogenicity Studies :Carcinogenicity studies are usually
needed only for drugs intended for chronic or recurring conditions
 Toxicokinetic Studies :These are typically similar in design to
PK/ADME studies except that they use much higher dose levels.
They examine the effects of toxic doses of the drug and help
estimate the clinical margin of safety

38.  Conduct initial non-clinical safety studies to assess
developability and potential risks for first
administration to humans
 Conduct additional studies to build confidence that
longer term clinical trials can be conducted
safely, and the medicine can be approved for use
To complete safety evaluation and
assist in dose selection for first clinical
trials, Safety Assessment has to:

39. Genetic damage? Carcinogenicity?
Aspects of a Safety Assessment
One dose Lifetime use
Acute Responses Chronic Effects
Reproduction
Development

40. Phase I:No blinding screening,open label & done in single
centre
• 20-40 max 50
• Healthy volunteers
• Sometimes patients are exposed to drug one
by one
Number of subjects
• Carried out by qualified clinical
pharmacologist & trained physician
• Dose is given in cumulative manner to
achieve the effective dose
Associated members
• P’kinetics,P’dynamics
• Emphasis of safety and tolerability
Purpose of study

41.  Phase II :Therapeutic exploration & dose ranging
 May be blind or open label (4centre’s or more)
• 100-400patients or volunteers
• According to specific inclusion and exclusion
criteria
Number of subjects
• Physicians
• These are trained as investigators
Associated members
• To establish therapeutic efficacy of drug ,dosage
regimen & ceiling effect in controlled settings
• Tolerability & p’cokinetics are studied as phase I
extension
Purpose of study

42.  Phase III :Therapeutic confirmation or comparison
 Done in multicentre
• Randamised double blind comparitive trails are done
• Indications are finalized & guidelines for therapeutic use are
formulated
• Submission of NDA for licensing is done who if satisfied grants
permission for marketing
Number of subjects
•500-3000
Associated members
• physicians
Purpose of study
• To establish value of
drug in relating to
existing one
• ADR’S on wide scale
in which P’cokinetic
data may be
obtained

43. Chemical Development
(CD), in collaboration with
Pharmaceutical Development
(PD), is charged with
delivering a cost
effective, efficacious
medicine...
Drug Substance (DS) Drug Product (DP)
Molecules to Medicines

44. 10-100g
10-100kgLab scale
Factory
scale

45. FDA:
US Food and
Drug
Administration
EMEA:
European
Medicines
Evaluation
Agency
MHLW:
Japan Ministry
of Health
Labour
& Welfare
Agencies provide
helpful insight into
study design
and doses
Reduce risk of
conducting long,
expensive studies
that don’t lead
to approval
May change
Phase III clinical
plan based on
feedback

46. Food and Drug
Administration
European
Medicines Agency
Ministry of
Health Labour
and Welfare
Therapeutic
Goods
Administration
Health Canada
International
Conference on
Harmonisation
Over 120 ‘International’
markets

48.  Build on knowledge – creative ideas
 Scilled medicinal chemists
 Dedicated project team
 Serendipity and luck - prepared mind
Chemistry
Pharmacolog
y
Toxicolo
gy Metabolism
PK

50. DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com
MOBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
web link
http://anthonycrasto.jimdo.com/
http://www.anthonymelvincrasto.yolasite.com/
http://www.slidestaxx.com/anthony-melvin-crasto-phd
https://sites.google.com/site/anthonycrastoorganicchemistry/sites-
--my-own-on-the-net
http://anthonycrasto.wordpress.com/
http://organicchemistrysite.blogspot.com/
http://www.mendeley.com/profiles/anthony-melvin-crasto/
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