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1. Drug Discovery and Development
How are drugs discovered and developed?

2. Overview
Outline here the fundamental concepts and processes of drug discovery
Drug discovery
Pre clinical study
Investigational New Drug
Clinical research
New Drug Approval Process
Marketing

3. Drug Discovery and Development
Drug discovery
Pre clinical study
Clinical research
Marketing
IND
NDA

4. Drug Discovery Process
Lead
Discovery
Pre-
clinical
Clinical
Review/
Approval
Post
Marketing
Number of years:
2-3 2-3 5-8 1-2
Number of subjects:
Ph I Ph II Ph III Ph IV
<50 <500 <5-5000 100s- 1000s
Cost
$1
Billion

5. Process for Successful Molecule
Phase 1
5-10,000 Molecule
Phase 2
250 Molecule
Phase 3
5 Molecule
NDA
1 Molecule

6. 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
FDA approval
(2-3 years)
Drug Discovery Process

7. The Steps Involved In Drug Discovery
Choose a Disease
Target Identification
Target Validation
Lead Identification
Lead Optimization
Preclinical studies
Clinical Studies
Marketing

8. Choosing a Disease
Number of deaths
Causes of death in
developed countries
Number of deaths
HIV-AIDS 2,678,000 Ischaemic heart disease 3,512,000
Lower respiratory
infections
2,643,000
Cerebrovascular
disease
3,346,000
Ischaemic heart disease 2,484,000
Chronic obstructive
pulmonary disease
1,829,000
Diarrhea 1,793,000
Lower respiratory
infections
1,180,000
Cerebrovascular disease 1,381,000 Lung cancer 938,000
Malaria 1,103,000 Stomach cancer 657,000
Tuberculosis 1,021,000
Hypertensive heart
disease
635,000
Chronic obstructive
pulmonary disease
748,000 Tuberculosis 571,000

9. Target Identification
Most of the drugs act on the cellular receptor or biological molecules in the body, which are associated with disease, is known as
Targets.
Various methods are used to identify target.
Interactions and role of target in disease are studied.

10. TARGET IDENTIFICATION
PROTEINS
Hormones Receptors Enzymes
Ion
Channels
DNA
RNA AND
RIBOSOMES
Drug targets fall into one of three main classes
Most current drugs are aimed at protein targets. However, current existing
therapies only hit about 400 different drug targets out of an estimated pool ten
times this size.

11. Potential Drug Targets

12. Potential Drug Targets
Agonist Agonist Agonist AgonistNa
Na
Activation of
conductance
G- Protein
Activation
Generation of
Second Messenger
Activation of
cell signaling
Phosphorylation of Tyrosines on
key signaling Molecules
Activation of cell
Signaling
Transport to the Nucleus
Activation of transcription
and translation

13. Target Validation
To identify the most useful target
Compare target in association with specific
disease
Design and execute relevant studies to identify
the target

14. Lead Identification
Lead molecule - A
molecule that is
believed to have
potential to treat
disease.
Scientists compare
standard drug in
the specific disease
with new molecule
to determine the
successful action.
Leads are
developed as
collections ,
libraries, individual
molecules etc.
Evaluation is done
to confirm it’s
effect on the
target.

15. Lead Identification -Process
1.Computer-
aided Drug
Design
(CADD) And
Structure-
based Drug
Design
(SBDD)
2..Virtual (In-
silico)
Screening
Leads to HITS
3.Synthesis
And
Combinatori
al Chemistry
4.IN SILICO
Predictive
Toxicity
5.Assay
Development
—HTS Leads
to LEAD
Compound
Lead Identification

16. Tools for Drug Discovery
x-ray
crystallography
NMR
Computer-
aided drug
design (CADD)
and structure-
based drug
design (SBDD)

17. 1.Computer-aided Drug Design (CADD) And
Structure-based Drug Design (SBDD)
IN SILICO SCREENING
SCREENING THROUGH CADD/SBDD
HITS
COMBINATORIAL CHEMISTRY
HIGH THROUGHPUT SCREENING
LEADS

18. 2.Virtual (in-silico) screening
Virtual (in-silico) screening sifts through large numbers of compounds
based on a user-defined set of selection criteria.
Physical property
such as
molecular weight
or charge
Chemical
property such as
number of
hetero-atoms,
number of
hydrogen-bond
acceptors or
donors
Three
dimensional
description of a
binding pocket of
the target
protein, including
chemical
functionality and
solvation
parameters
Docking of
ligands to a
target site

19. 3.Hits to Synthesis and Combinatorial
Chemistry
1 • Hits to Synthesis and Combinatorial Chemistry
2
• New Compounds are supplied by chemist
• New compounds are converted to large amount of precursor
3
• By rule of thumb, one chemist synthesizes, purifies, and
characterizes about 100 novel compounds per year
• Which give 10,000 compound to develop one drug

20. Mutagenicity
Carcinogenicity
Reproductive Toxicity
4.IN SILICO Predictive Toxicity

21. 5.Assay Development—HTS
Development of Assay
Screening of compounds
Primary screens will
identify Hits
Confirmation screens
and counter screens
will identify leads out of
the pool of hits
High-throughput
screening (HTS) aims to
quickly review the
goings-on of a large
number of compounds.

22. Lead Optimization
• Quantitative
structure
activity
relationship
(QSAR)
Lead
Optimization
• Structure
Activity
Relationship
Lead
Optimization
• Animal
PK/PD
Lead
Optimization
• Toxicity
Lead
Optimization
• Formulation
and Delivery
Lead
Optimization

23. 1.Quantitative structure activity
relationship (QSAR)- Lead Optimization
Quantitative Structure
Activity Relationship (QSAR)
The derived
function
group is used
as a guide to
select best
candidate for
drug design.
Reflects the
property of
binding
cavity on
protein
target.
Derive a
functional
group that
links
biological
activity

24. 2.Structure Activity Relationship
Pharmacological
assay for lead
assessment
Optimization of
pharmacological
properties
Determination of
Potency,
selectivity and
MOA
Data into next
optimization
cycle
Lead Optimization

25. 3.Animal PK/PD-Lead Optimization
Animal pharmacokinetics (ADME) and
pharmacodynamics (PD) assess the general
pharmacology and mechanisms of action of
drugs..
Lead molecules are administered via different
routes: intravenous (iv), intraperitoneal (ip),
subcutaneous (sc), intramuscular (im), rectal,
intranasal (IN), inhalational, oral , trans
dermal, topical, etc
The main models used are rodents including
mouse and rat, but larger animals such as
dogs, pigs, and, more rarely, monkeys, are also
used under certain circumstances.

26. 3.Animal PK/PD-Parameters
• PK/PD studies rely heavily on analytical methods and
instrumentation. The recent innovation and progress in
mass spectroscopy, (whole-body) imaging, and
chromatography technology (HPLC, LC-MS, GC-MS) have
tremendously increased the quantity and quality of data
generated in PK/PD experiments.
A large number of parameters is assessed. Here is a
partial list:
(ADME); bioavailability (F) and protein binding; stability
and half-life (t1/2); maximum serum concentration
(Cmax); total exposure or area under the curve (AUC);
clearance (Cl); volume of distribution (Vd); drug drug
interactions; onset of drug action; multicompartmental
analysis of blood, liver, and other tissues.

27. Principles and applications of LC-MS in
new drug discovery

28. 4.Toxicity-Lead Optimization
The toxicity is the degree to which a substance or mixture of substances can
harm human or animals.
Acute Toxicity
Acute toxicity involves harmful
effects in an organism through
a single or short-term
exposure.
Chronic Toxicity
Chronic toxicity is the ability of
a substance or mixture of
substances to cause harmful
effects over an extended
period.

29. Lead
Lead
Formulation and Delivery

30. Formulation and Delivery

31. Preclinical Studies

32. Pre-Clinical Studies
Once the drug is designed it have to be tested
In vitro [ in laboratory conditions-glass wares].
In vivo [in animals (rodents and non rodents, lab
models)].

33. Difference between In Vivo And In
Vitro
In Vivo
In Animals
Generates
Pharmacokinetic,
Pharmacodynamic and
toxicokinetic data
Gives an understanding
of dose, dose range, side
effects, drug receptor
binding capabilities,
In Vitro
In Test Tubes
Generates
Pharmacodynamic
data
Gives an understanding on
pharmacological action of
drug, mechanism of action
of drug,Mutagenicity

34. Objective of Preclinical Studies
Pharmacokinetic Studies
Toxicokinetic Studies
Pharmacodynamic Studies

35. Importance Of Pharmacokinetic
Studies
Research and selection
of a promising molecules
Formulation Dosage
Toxicology and safety
assessment
Dosing recommendation
for age groups and
subgroup population
Effect of meals and
dosing

36. Importance of Toxicokinetic Studies
Toxicokinetic Studies
Single dose
Toxicity
Repeated-
dose
toxicity
Reproductive
toxicity
Genotoxic
potential
Carcinogenicity
Safety
pharmacology.

37. Coordination of preclinical and clinical
studies.

38. Coordination of
preclinical and clinical
studies
Drug information journal Vol. 35, pp. 321-336,2001

39. Investigational New
Drug Application
(INDA)
•What is an INDA?
Sponsors
IND
FDA
To initiate the
conduct of clinical
trials

40. Contents of INDA
INDA
Table of
content
Cover Letter
Introductory
Statement and
General
Investigational
Plan
Investigator’s
Brochure
Clinical Protocol
Chemistry
Manufacturing
and Controls
Information
Pharmacology
and Toxicology
Information
Previous Human
Experience
Additional
Information

41. Clinical Trials
Phase I:- Studies in
normal healthy
volunteers to
understand
pharmacokinetics
Phase II: Dose
ranging efficacy
safety studies to
determine the
optimal dose for a
particular
indication
Phase III:Large
scale multicentre
comparative
studies to assess
efficacy safety of
the study drug v/s
currently accepted
treatment.
Phase IV: Post
Marketing Studies.

42. Clinical Trial – Phase I
Phase 1
Done in 20-
100 subjects.
Usually
healthy
volunteers
To understand the
metabolic and
pharmacological
action of drug
Maximum Test
Dose
determination,
etc
Provide
information of
pharmacology
effects of drug.
Safety is the
major aspect
of study.

43. Types of Phase I Trial:

44. Phase II
Phase 2
Rigid and well-
controlled
small
population
between
100-300.
Double blind
studies using
placebo or
standard
treatment are
done.
Efficacy and
safety are
evaluated.
Pharmacokinetic
and other
pharmacological
studies are
done.

45. Types of Phase II Studies
Phase 2 Trials
Phase IIA
is specifically
designed to assess
dosing
requirements (how
much drug should
be given).
Phase IIB
is specifically
designed to study
efficacy (how well
the drug works at
the prescribed
dose(s)).

46. Phase III
Phase 3
Done in a
large
population-
above 300
Evaluation of
efficacy and
safety profile
(initial risk
benefit
assessment)
Identification
of the
disease sub
types for
which drug is
effective.
Comparison
with other
standard
drugs.
Pharmacokin
etics with
others drugs
and Quality
of life
(depends)
are
evaluated.

47. Done while the New Drug Application (NDA) is submitted
to FDA.
Studies which start pre-launch but which are not
intended to form part of Regulatory dossier are referred
to as Phase III-b.
The data of this study also submitted to FDA.
Types of Phase III

48. Difference between Phase I,II and III
Trials
Phase 1
• Safety
• Dose Ranging
Phase 2
• Safety
• Efficacy
• Dose
• Route
Phase3
• Efficacy vs.
standard
• Defined endpoints

49. The formal request to be allowed to
market a drug.
Sponsor submit NDA to FDA after phase III
trials are competed.
Have to submit everything that is known
about the drug to date, all protocols, case
report forms.
Regulation for NDA are found in 21 CFR
314.
New Drug
Application (NDA)

50. New Drug Application (NDA)
Drug Discovery
and
development
Preclinical Clinical FDA Manufacturing
Initial
Synthesis of
chemical
Research and
development
FDA Expects
Review data
Drug appears
on the
market
Lab and
animal Studies
Testing in
healthy
volunteers
Company
address FDA
Concerns
Post
marketing
Surveillance
IRB
Testing in
disesed
individual
Advisory-
Hearing may
be called
Follow up
Studies and
inspection
Large scale studies
with diseased
individuals
IND NDA FDA

51. Phase IV

52. S.No Phases No of People
Population
Group Safety/Efficacy Goal
1 Phase I 20-100
Healthy
Individuals Safety
 The main goal of a Phase 1 trial is
to discover if the drug is safe in
humans. Researchers look at the
pharmacokinetics
of a drug. How is it absorbed? How
is it metabolized and eliminated
from the body?
 They also study the drug’s
Pharmacodynamic: Does it
cause side effects? Does it produce
desired effects?
 Dose ranging studies
 ,Safety Studies
2 Phase II 100-500
Diseased
Individuals Safety and efficacy
 In Phase 2 trials researchers
evaluate the candidate drug’s
effectiveness
Examine the possible short-term
side effects (adverse events) and
risks associated with the drug.
 Researchers also analyze optimal
dose strength and schedules for
using the drug.

53. S.No Phases No of People
Population
Group Safety/Efficacy Goal
3 Phase III 1000-5000
Diseased
Individuals
Safety and efficacy
and benefit-risk
relationship
 This phase of research is key in
determining whether the drug is safe
and effective.
 It also provides the basis for labeling
instructions to help ensure proper
use of the drug (e.g., information on
potential interactions with other
medicines).
4 Phase IV >5000
Real Life
Population
Ongoing monitoring
of safety of drug
 These trials can be set up to
evaluate long-term safety or how the
new
medicine affects a specific subgroup
of patients.