1. DRUG DISCOVERY

2. DRUG DISCOVERY
• The processes of new drug discovery and
development are long, complicated and
dependent upon the expertise of a wide
variety of scientific, technical and
managerial groups.

3. Why are new drugs needed?
• unmet medical need; new diseases (AIDS, Alzheimer’s;
obesity); low efficacy (dementia, cancer); side effects
(antidepressants, antipsychotics)
• downstream health costs; (Alzheimer’s; spinal injury)
• cost of therapy; (Viagra, Interleukins)
• costs to individual/country; (depression)
• sustain industrial activity; pharmaceutical industry
employs thousands and makes a massive contribution to
overseas earnings); patent expiry

4. Approaches to drug discovery
• Historical; cinchona (quinine) & willow barks (aspirin);
chinese medicine currently.
• Study disease process; breast cancer (tamoxifen);
Parkinson’s disease (L-dopa)
• Study biochem/physiological pathway; renin/angiotensin
• Develop SAR to natural compound; beta-adrenoceptors
(propranolol), H2-receptors (cimetidine)
• Design to fit known structurally identified biological site;
angiotensin-converting enzyme inhibitors
• By chance (serendipity); random screening (HTS);
penicillin; dimenhydramate; pethidine
• Genomics; identification of receptors; gene therapy;
recombinant materials

5. The changed context of drug discovery
and development
The 1800s: natural sources; limited possibilities; prepared
by individuals; small scale; not purified, standardised or
tested; limited administration; no controls; no idea of
mechanisms.
The 1990s and 2000: synthetic source; unlimited
possibilities; prepared by companies; massive scale;
highly purified, standardised and tested; world-wide
administration; tight legislative control; mechanisms
partly understood, still understanding.

7. The New Drug Development Process

8. RRR

9. • About 2.6m animals/y used in procedures in UK (11.6m
in Europe)
• Likely to increase; more research, more targets, genetic
capability
• 3Rs -- 3Rs -- 3Rs
• REPLACEMENT: use non-animal tests if possible
(cheaper, less trouble, less variable but not possible for
everything at this time)
• REDUCTION: get the statistics right, don’t replicate work
unnecessarily, don’t overbreed
• REFINEMENT: reduce suffering and severity of
procedure, pay attention to housing, stress, husbandry
and rich environments, proper analgesia and pre- and
post- operative care

10. There are two types of Research: Basic and
Applied
• Basic Research: discovering new facts about how things work, how
they are made, or what causes a biological event to occur. Basic
research can explore a topic, explain a topic or describe a topic.
• For Example: A researcher discovered that genes can be turned off
or on by small RNA molecules in the body. This study was
conducted on worms. It led to the Nobel Prize in 2006.

11. “Basic” vs. “Applied”
Research
• Applied Research: Taking the
information discovered in basic research
and investigating how to use it to treat
and prevent sicknesses.
• Example: A researcher uses the
information about turning genes off and
on to find a drug that is used to turn off Segment of DNA.
Many such
genes that cause diseases and disorders
segments act as
in humans genes

12. Process of Drug Discovery
• Target Identification
• Target Validation
• Lead Identification
• Lead Optimization
• Preclinical Pharmacology and Toxicology

13. Target Identification
• Identifying targets include
protein expression, protein
biochemistry.
• Sequence analysis,
positional cloning, functional
cloning.
• Important to determine
whether the novel targets are
actually relevant to the
physiology of the disease.

14. Target Validation
• Target identified will affect an appropriate biological
response
• CHEMOGENOMICS;defined as the discovery and
description of all possible drugs to all possible targets.
• Chemical Genetics; involves the use of chemical probes
to understand some specific features of biology and can
be viewed as subset of chemogenomics.
• LIMITATIONS;Compensatory mechanism of the
organism.

15. Lead Identification
• “lead compound”: structure that has some activity
against the chosen target, but not yet good enough to be
the drug itself.
Virtual Pharmacaphore
Screening Mapping Docking
Chemoinformatics QSAR Chemical Genetics

16. • The pharmacophore is the precise section of the
molecule that is responsible for biological activity.
• This may enable one to prepare a more active molecule
• This may allow the elimination of “excessive”
functionality, thus reducing the toxicity and cost of
production of the active material
• This can be done through synthetic modifications

17. Lead Optimization
• Once a lead has been discovered, it is
important to understand precisely which
structural features are responsible for its
biological activity.

18. Pre-Clinical Pharmacology and
Toxicology
• TOXICOLOGY
• Thalidomide was developed by German pharmaceutical company
Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at
least 40 names. Thalidomide was chiefly sold and prescribed during the
late 1950s and early 1960s to pregnant women, as an antiemetic to combat
morning sickness and as an aid to help them sleep. Before its release,
inadequate tests were performed to assess the drug's safety, with
catastrophic results for the children of women who had taken thalidomide
during their pregnancies
• Antiemetic = a medication that helps prevent and control nausea and
vomiting

19. Birth defects
caused by use of thalidomide

20. • Preclinical trial - a laboratory test of a new
drug or a new medical device, usually
done on animal subjects, to see if the
hoped-for treatment really works and if it is
safe to test on humans.

21. There are several steps involved with doing a Pre-
Clinical Trial
• File for approval as an Investigational New Drug (IND)
5
•
Establish Effective and Toxic Doses
4
3 Screen the Drug in the Assay
2 Develop a Bioassay
1
Indentify a Drug Target

22. Scientific Aspects of Clinical Trial
Phases of Clinical Trial
• Phase I (Human pharmacology and safety): First in
man  safety
• Phase II (Therapeutic exploration and dose ranging):
First in patient dose, dosage form
• Phase III (Therapeutic confirmation/comparison) :
Efficacy, ADRs
• Phase IV (Post marketing surveillance) : Evaluation in
the real clinical setting

23. Phase I
• Objectives
1. To assess a safe & tolerated dose
2. To see if pharmacokinetics differ much from animal to man
3. To see if kinetics show proper absorption, bioavailability
4. To detect effects unrelated to the expected action
5. To detect any predictable toxicity
– Inclusion criteria
– Healthy volunteers : Uniformity of subjects: age, sex,
nutritional status [Informed consent a must]
– Exception: Patients only for toxic drugs Eg AntiHIV, Anticancer
– Exclusion criteria
– Women of child bearing age, children,

24. Phase II
• First in patient [ different from healthy volunteer]
• Early phase [20 – 200 patients with relevant disease]
– Therapeutic benefits & ADRs evaluated
– Establish a dose range to be used in late phase
– Single blind [Only patient knows] comparison with standard drug
• Late phase [ 50 – 500]
– Double blind
– Compared with a placebo or standard drug
• Outcomes
– Assesses efficacy against a defined therapeutic endpoint
– Detailed P.kinetic & P.dynamic data
– Establishes a dose & a dosage form for future trials
• Takes 6 months to 2 years [ 35% success rate

25. Phase III
• Large scale, Randomised, Controlled trials
• Target population: 250 – 1000 patients
• Performed by Clinicians in the hospital
• Minimises errors of phases I and II
• Methods
– Multicentric  Ensures geographic & ethnic variations
– Diff patient subgroups Eg pediatric, geriatric, renal impaired
– Randomised allocation of test drug /placebo / standard drug
– Double blinded:
– Cross over design
– Vigilant recording of all adverse drug reactions
– Rigorous statistical evaluation of all clinical data
• Takes a long time: up to 5 years [25% success

26. Phase IV or Post marketing
Surveillance
• No fixed duration / patient population
• Starts immediately after marketing
• Report all ADRs
• Helps to detect
– rare ADRs
– Drug interactions
– Also new uses for drugs [Sometimes called Phase V]

27. Clinical Trial: Legal & Procedural
aspects
Elements of a Clinical Trial
• Aim or objective
• Protocol : study design
• Ethics committee clearance
• Regulatory approval whenever required
• Informed consent
• Implementation of protocol
• Collection of data
• Compilation of data, analysis and interpretation
• Report writing

28. Participating Parties in Clinical Trial
1. Patient / Healthy volunteer: Subject of the trial
2. Clinical Pharmacologist, Clinical Investigator & team: [Qualified and
competent] Conducts the clinical trial; reports all adverse events
3. Institution where trials are held : [Approval required] Provides all
facilities
4. Ethical Review Board or Institutional Ethical Committee:
-Supervises and monitors every step;
– Safeguard the welfare and the rights of the participants
– 5. Sponsor
– Pays for all expenses;
– Appoints competent investigators,
– Ships all drugs for the trial,
– Files all papers to legal / regulatory authorities,
6. Regulatory Authorities:
Legal authority on the outcomes of the trial

29. THANKS