Drug designing

1. TRP 311
Dept. of Veterinary Pharmacology and
Toxicology
Sharafudheen K A
14-BVM-95

2. INTRODUCTION
 Drug discovery and development of a new drug is a costly,
time consuming and complicated process.
 It involves scientific experts from various disciplines.
 Cost nearly $ 800 million to $1.7 billion and takes an
average of 10-12 years.
 It was estimated that out of 5000 drugs identified during
discovery process , only five are considered safe for testing
after preclinical evaluation .Only one of these drug is
approved as marketed drug after clinical testing

3. DRUG DISCOVERY
 Process by which new drugs discovered and/designed for
some therapeutic efficacy.
 Once a drug has been identified for therapeutic value in
discovery process, it will begin the process of drug
development.
 New approaches like target specific molecular designing
are increasingly used for drug discovery.
 Discovery phase that includes a lead identification step
followed by lead optimization resulting in a drug candidate
selection

4. HISTORY OF DRUG DISCOVERY
 In the early days therapeutic drugs were created from the
derivative of medicinal plants.
 Drug serendipity.
 Classical pharmacology in drug discovery.
 Reverse pharmacology in drug discovery.

5. CLASSICAL PHARMACOLOGY
 phenotypic screening of chemical libraries of synthetic small
molecules, natural products or extracts to identify substances that have
a desirable therapeutic effect.
 Using the techniques of medicinal chemistry, the potency, selectivity,
and other properties of these screening hits are optimized to produce
candidate drugs.
 Classical pharmacology traditionally has been the basis for the
discovery of new drugs.
 Compounds are screened in cellular or animal models of disease to
identify compounds that cause a desirable change in phenotype. Only
after the compounds have been discovered, an effort is made to
determine the biological target

6. REVERSE PHARMACOLOGY
 target-based drug discovery: modulation of the activity of a
specific protein target will have beneficial therapeutic effects.
 Screening of chemical libraries of small molecules is then used to
identify compounds that bind with high affinity to the target. The hits
from these screens are then used as starting points for drug discovery.
 This method became popular after the sequencing of the human
genome which allowed rapid cloning and synthesis of large quantities
of purified proteins.
 This method is the most widely used in drug discovery today.
 Differently than the classical pharmacology, with the reverse
pharmacology approach in vivo efficacy of identified active compounds
is usually performed in the final drug discovery stages

7. METHODS OF DRUG DISCOVERY
Molecular designing
Molecular manipulation
Random screening
Bio prospecting
Drug serendipity
Active metabolites
Genetic engineering

8. MOLECULAR DESIGNING
 Structuring or designing of a new substance to fulfill specific biological task.
 Most rational form of drug development and research in recent times.
 In this technique initially identify a target , then subsequently design molecule which can
interact with target which might be helpful in the treatment of disease.
 With the invent of computer and microelectronics , new methods are being applied to
molecular designing.
 Computers are now used to store large no of chemical structures from which new
molecules can be easily designed.
 Computers can visualize receptor and can design matching drug molecule.
 Allopurinol, an analogue of xanthine.

9. MOLECULAR MANIPULATION
 Chemical modification of known molecule.
 Used in the discovery of new drugs or screening of natural
products for biological activity and subsequent semi-synthetic
production.
 Can use natural drugs from plant and animal sources as a
starting material in the creation of slightly different molecule or
totally different agent.
 Superior pharmacological properties and fewer side effect.
 Morphine and sulphanilamide.

10. RANDOM SCREENING
 Evaluation of drug for different type of biological activity
 Chemical substances subjected to no of tests to determine
it’s different type of pharmacological effect.
 Only one in 4000-5000 new chemical substance screened
marketed for clinical use.
 Antibacterial drug tetracycline was discovered through
random screening.

11. BIO PROSPECTING
 Exploration of biological diversity for the molecules to be
used as drug or other commercial product.
 Important procedure for discovering new drugs for
centuries.
 Biodiversity like plants , insect , algae , and microorganism
have been explored.
 Aspirin from willow tree , Tamoxifen from bark of yew,
antineoplastic drugs.

12. DRUG SERENDIPITY
 Accidental discovery.
 Led to introduction of many useful drugs in therapeutics.
 Alexander Fleming discovered penicillin while observing
mould contamination in culture.
 Cardiac antiarrhythmic effect of lidocaine , tranquilizing
effect of chlorpromazine , anti-baldness effect of minoxidil.

13. ACTIVE METABOLITES
 Many drugs have been found to convert to one or more active
metabolites in the body.
 Possess stronger action and therapeutic advantages over parent
compounds.
 These active metabolites are marketed as new therapeutic agent.
 Better efficacy , potency or pharmacokinetics or lesser side
effects.
 Paracetamol , an active metabolite of phenacetin.

14. RECOMBINANT DNA TECHNOLOGY/GENETIC
ENGINEERING
 Manipulation of genetic elements which results in
alterations to protein.
 A no of new and selective drugs can be produced.
 Yielded useful recombinant vaccines like pseudo rabies
vaccine , recombinant canine distemper virus vaccine etc.
 Examples : recombinant human erythropoietin ,
recombinant human insulin etc.

15. TARGET SELECTION
Target selection in drug discovery is defined as the decision to
focus on finding an agent with a particular biological action that is
anticipated to have therapeutic utility — is influenced by a
complex balance of scientific, medical and strategic considerations.
Target is generally a naturally existing cellular or molecular structure
involved in some disease process.
Potential drug targets are not necessarily disease causing but must by
definition be disease modifying.
Design molecule which can interact with target and might be helpful in
the treatment of disease.

16. Target Validation - Linking Targets
to Diseases and Treatments
 Target validation is a series of activities, which aim to
build confidence that a drug which acts by modifying
the function of the target will deliver the efficacy and
safety required
 Degree of target validation varies, depending upon the
nature of the disease, type of target etc.
 A target is never fully validated until a drug acting on it
works in patients!

17. BIOINFORMATICS
 Bioinformatics is a branch of molecular biology that
involves extensive analysis of biological data using
computers, for the purpose of enhancing biological
research.
 It plays a key role in various stages of the drug discovery
process including
 target identification
 computer screening of chemical compounds and
 pharmacogenomics

18. LEAD DISCOVERY
 A lead compound in drug discovery is a chemical
compound that has pharmacological or biological activity likely
to be therapeutically useful, but may still have suboptimal
structure that requires modification to fit better to the target
 A lead compound may arise from a variety of different sources.
Lead compounds are found by characterizing natural
products,employing combinatorial chemistry, or by molecular
modeling as in rational drug design.
 Lead compounds are often tested by high-throughput
screenings.

19. LEAD OPTIMISATION
 Optimise lead molecules to identify a single compound with potential
to reach the clinic with:
- right properties – potency, selectivity, PK etc.
- low probability of failure in development
 Aiming to combine all desired properties into one molecule
 A key focus is the reduction of attrition in clinical studies by
improving our understanding of key risk factors such as safety and
efficacy failures and the development of technologies to enable these
factors to be identified and addressed in lead optimization.

20. HIGH THROUGPUT SCREENING
 High-throughput screening (HTS) is a method for
scientific experimentation especially used in drug discovery.
 Using robotics, data processing and control software, liquid handling
devices, and sensitive detectors, High-throughput screening allows a
researcher to quickly conduct millions of chemical, genetic, or
pharmacological tests.
 Through this process one can rapidly identify active compounds,
antibodies, or genes that modulate a particular biomolecular pathway.
 The results of these experiments provide starting points for drug design
and for understanding the interaction or role of a particular
biochemical process in biology

21. In silico screening
Computer simulated screening of chemicals
Helps in finding structures that are most likely to bind to
drug target.
Filter enormous Chemical space
Economic than HTS

22. DRUG DEVELOPMENT
 Entire process of bringing a new drug to market , once a candidate drug has
been discovered.
 Focus on satisfying the regulatory requirements of candidate drug.
 Once the potential drug molecule has been selected or identified, it is
progressed further for the process of drug development. In this step various
parameters of the lead compound can be assessed on different fronts such as in
vitro assays (experimental analysis), in vivo models (animal studies), and in
silico approaches (software based).
 In vitro studies involve biochemical estimation, drug susceptibility tests, and
toxicity assays.
 invivo studies help in understanding pharmacokinetic and pharmacodynamic
parameters.

23. REGULATORY AGENCY
• Overlooks before and during various phases of product
development and its marketing.
• The drug is tested:
• Pre-clinical testing (laboratory and animals)
Pharmacology and toxicology
• Clinical testing (clinical trials in humans)
dose regime, safety and efficacy
consistency and reproducibility

24. PRE DEVELOPMENTAL STAGE
 Some basic research data are produced before the actual
drug development stage starts.
 physicochemical analysis
 Screening
 pharmacological profile.
 short term toxicity test.

25. DEVELOPMENTAL STAGE
 Once laboratory tests have indicated useful
pharmacological activity and acceptable toxicity
profile , candidate drug enters developmental stage.
Divided into two sub stages
preclinical development(on experimental animals)
clinical development(on target species)

26. PRECLINICAL DEVELOPMENT
Objectives
To determine product’s ultimate pharmacological &
safety profile
To estimate safety testing dose of drug for clinical trials
in target species.
During which, drug undergoes
- Pharmaceutical studies
- Pharmacological studies
- Toxicity studies
Acute toxicity
Sub acute toxicity
Chronic
toxicity(teratogenic,
carcinogenic , mutogenic ,
fertility and reproductive
studies

27. CLINICAL DEVELOPMENT
It begins when preclinical data have established the
apparent safety and efficacy of candidate drug.
To make candidate for therapeutic use in target species
Help in registration and marketing.

28. CLINICAL STUDIES
To ascertain therapeutic effect of drug.
To specify indications and contraindications according
to species and age.
To identify the side effects of drug in target species.
To ensure safety of drug under general conditions of
use.

29. Clinical Testing – Phase I
Clinical pharmacological evaluation
Conducted in small no of healthy target animals
(usually 20-100)
Identify the metabolic and pharmacological effect in
target species.
Determine the side effect associated with increasing
doses.

30. Clinical Testing – Phase II
 Controlled clinical evaluation.
 Conducted in relatively large no of target animals (several
hundred)
 Strictly controlled and closely monitored trials.
 Ascertain the safety and efficacy of of new drug in target
species.
 Evaluate the drug toxicity and therapeutic usefulness of
new drug.

31. Clinical Testing – Phase III
Extended clinical evaluation.
Include several hundred to several thousand animals.
Large scale extensive clinical study.
Evaluate the effect of drug in target animals at different
locations.

32. Studies on drug residues
and safety to human
Studies on environment
safety
 Safety to humans.
 Drug residues.
 Withdrawal time.
 Effect on soil , water and
vegetable life or animal.
 Must not concentrate along
food chain.
 Must not accumulate in
environment.

33. GETTING REGULATORY APPROVAL
 If the results of all the previous testing is positive, then the
pharmaceutical company files an NDA for drug licensing
and marketing.
 NDA contains all of the information gathered during
preclinical to phase III
 NDA can be thousands of pages long.
If approved by DCI , drug is marketed for general use.

34. POST MARCKETTING SURVEILANCE
Study made on patients by participating clinician.
To find out the safety profile in patient across the world.
To determine certain unusual type of adverse reaction and
toxic effects on long-term use of the drug.
Also determines the drug utilization pattern , additional
therapeutic effects , etc.
Study continues till the drug is used.

35. ORPHAN DRUGS
 An orphan drug is a pharmaceutical agent that has
been developed specifically to treat a rare medical
condition, the condition itself being referred to as an
orphan disease.
 Not developed into usable medicine because the cost
involved in manufacturing is very high and limited no
of patients.
 Follow the same regulatory path as any other
pharmaceutical agent.

36. CONCLUSION
 Despite advances in technology and understanding of
biological system at molecular level , discover is still a
lengthy , expensive , difficult and inefficient process with
low rate of new therapeutic discovery.
 Historically , many successful compound found by group of
less than 50 scientists , small compared with many
industrials group today.
 One of the greatest challenges currently facing
pharmaceutical companies is to assimilate vast amount of
information generated by genomic and proteomic research
into drug discovery programmes.

37. REFERENCE
 Harpal Singh Sandhu , New drug discovery and development ,
Essential of Veterinary Pharmacology and therapeutics : 117-116.
 S . K . Gupta , High through screening for high speed drug discovery
and New screening method , Drug Screening Methods : 1-33.
 JIBEN ROY ,Drug discovery and development, An Introduction to
pharmaceutical science : 49-52.
 Takenaka T ( Septemper 2001) , “ classical vs reverse pharmacology in drug
discovery , BJU International.
 Daniel E. Salazar, Glenn Gormley Modern drug discovery and
development , Clinical and Translational Science (Second Edition), 2017
: 719-743

38. THANK YOU