1. Drug Discovery & Development
PHC 311
Lec. 1

2. Reem Al-Wabli
Office no.; S67 ;

3. Course Description:
This course is designed to give pharmacy students an overview of the process that involves the discovery of new drugs. The course covers the drug discovery (DD) process from the beginning through the final stages of clinical trials. The various stages of identifying and selecting a target, selecting and optimizing a lead compound, carrying out of in-vitro and in-vivo testing to determine biological activity and/or toxicity. The course will focus on the role of the pharmacist, as a scientist involved in discovering and developing new drugs in the pharmaceutical industry.

4. References
1. Gareth Thomas Medicinal Chemistry, An Introduction, 2nd Edition. Wiley-Interscience (2008)
2. Graham L. Patrick, An Introduction to Medicinal Chemistry, 3ed Ed.; Oxford University Press (2005))

5. Credits Type 25 Midterm I 1 Midterm II 2 10 Term Activity* 4 40
Final exam 5
*Homework and Classroom Assignments and Discussion

6. Topics to be covered Introduction to Drug Discovery
Overview of the Drug Discovery Process
Target ID & Selection
Lead ID and Optimization
Fragment-Based, Structure-Assisted Lead Generation
Assays and Animal Models in Drug Discovery
In-vitro & In-vivo Testing
ADME Evaluation
Clinical Trials
Epidemology
Pharmacogenetics

7. Medicinal Chemistry Folklore
Medicinal chemistry is the science that deals with the discovery of therapeutic chemicals and their development into useful medicines
Medicinal chemistry has been practiced for thousands of years
The earliest written records of the African, Chinese, Indian, South American, and Mediterranean cultures describe the therapeutic effects of various plant parts.
Man has search for cures by chewing on bark, roots, leaves and berries.

8. Medicinal Chemistry is defined as an interdisciplinary science situated at the interface of organic chemistry and life sciences (such as biochemistry, pharmacology, molecular biology, immunology, pharmacokinetics and toxicology) on one side and chemistry-based disciplines (such as physical chemistry, crystallography, spectroscopy and computer-based information technologies) on the other.
Medicinal Chemistry
Chemistry based
disciplines
Organic Chemistry
Life Sciences

9. Medicinal Chemistry
Terms more or less synonymous with medicinal chemistry
Pharmacochemistry
Molecular pharmacochemistry
Drug design

10. Definition and Objectives
Medicinal chemistry relates to the design and production of compounds that can be used in medicine for the prevention, treatment or cure of human and animal diseases.
Medicinal chemistry covers three critical steps:
A discovery step: consisting of the identification and production of new active substances usually called lead compounds. Leads can originate from synthetic organic chemistry, from natural sources or from biotechnological processes.
An optimization step: that deals mainly with the synthetic modification of the lead structure in order to improve potency, selectivity and lessen toxicity. Its characteristics are the establishment and analysis of structure-activity relationships (SARs).

11. Definition and Objectives (cont.)
A development step consisting of:
the optimization of the synthetic route for bulk production.
modification of the pharmacokinetic and pharmaceutical properties of the active substance to render it suitable for clinical use. This may cover optimization of properties associated with:
Chemical formulation
Solubility
Elimination of unpleasant taste or irritation
Reduction of pain at site of injection

12. Drugs are strictly defined as chemical substances that are used to prevent or cure diseases in human, animals and plants.
The word drug, therefore, imposes an action-effect context within which the properties of a substance are described. For example when a drug is defined as an analgesic, it means that it is used to treat pain ….. Thus a drug may described as having analgesic, vasopressor, anticonvulsant, antibacterial, …….…etc properties.
Medicinal chemist must excel in organic synthesis and understanding modern approaches to structure-activity analysis. Medicinal chemist are involved in the design, synthesis, optimization and selection of new lead compounds

13. Classification Systems
Drugs can be classified under the following categories:
1) The origin of the drug
2) The mode of action
3) The nature of the illness
4) The chemical structure

14. 1) The origin of the drug Classification Systems (cont.)
Drugs of natural origin can come from 4 sources.
Minerals: iodine, phosphates, calcium, sodium , iron
Animal kingdom: insulin, fish oils, biliary salts
Vegetable or plant origin: alkaloids, cardiac glycosides, anticancer agents
Genetic engineering and fermentation products.

15. Classification Systems (Cont.)
2) The mode of action (3 flavors)
Medicine that treat the cause of the disease termed “true drugs” or etiological drugs. Antibacterials, antifungals, antivirals and antiparasitics (chemotherapeutic drugs). Activity resides in their selective toxicity or the ability to destroy the invader without destroying the host. This includes also vaccines and preventive therapies.

16. 2) The mode of action (cont.)
Medicine that compensate for the deficiency (Substitutive drugs) to take the place of missing substances (vitamin therapy, insulin, i.v. rehydration during hemorrhages and diarrhea, long term treatment in Addison’s disease.
Medicine that alleviate the symptoms (Symptomatic treatments) to attenuate or neutralizes a disorder in a disease state (i.e. anesthestics, ibuprofen). As a rule this mode does not cure the patient but rather to render daily life more comfortable.

17. Classification Systems (Cont.)
3) The nature of the illness
The world health organization (WHO) in 1968 adopted this physiological classification which classifies drugs by the body system on which they act. EX. Cardiovascular, Diuretics, immunomodulators……….etc.
4) The chemical structure
A great area for synthetic chemist to learn

18. Practical Classifications
In practice the most powerful and useful system developed is known as the anatomical-therapeutic-chemical (ATC) system. The system is divided into 4 general groups according to the body system on which they act.

19. Common Medicinal Classifications
1) Pharmacodynamic agents:
Affecting normal dynamic processes of the body.
2) Chemotherapeutic agents:
Drugs inhibiting the development of various kinds of infesting host.
Agents acting on metabolic diseases and on endocrine function.
4) Agents acting on the central nervous system:
Psychotropic and neurological drugs.

20. Common Classification (Continued)
1) Pharmacodynamic agents—affecting normal dynamic processes of the body
Antiarrhythmics
Antianginals
Vasodilators
Antihypertensives
Antithrombotics
Antiallergic drugs

21. Common Classification (Cont.)
2) Chemotherapeutic agents: drugs inhibiting development of various kinds of infesting host
protozoa, microbes, fungi, virus
Antibiotics included in this class
3) Agents acting on metabolic diseases and on endocrine function
Anti-inflammatories
Antiarthritics
Antidiabetics
Hypolipidemic
Peptides
Steroid hormones

22. Common Classification (Continued)
4) Agents acting on the central nervous system: psychotropic and neurological drugs: Common drugs are:
Anti-depressants
Anti-psychotics
Anxiolytics
Anticonvulsants
Sedatives
Hypnotics
Analgesics
Anti-Parkinson’s drugs

23. Drug names: (nomenclature)
Chemical
6-Chloro-3,4-dihydro-7-sulfamoyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
Trade
Hydrodiuril®, Hydroaquil®, Esidrex®, Urozide®, Novohydrazide® etc. Many others
Generic
Hydrochlorothiazide

25. Sources of Drugs

27. The Lead Compound
A compound demonstrating a property likely to be therapeutically useful.
The level of activity and target selectivity are not crucial.
Used as the starting point for drug design and development.
Found by design (molecular modelling) or by screening compounds (natural or synthetic).
Need to identify a suitable test in order to find a lead compound.
Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound.

28. Methods for Drug Discovery
Without a lead compound (Serendipity).
Lead discovery:
Random screening.
Clinical Observations.
Drug Metabolism studies.
Rational approaches to lead discovery.
Computer Aided Design

29. Drug Discovery Without a Lead (Serendipity)
Penicillins: Fleming
Bacteria lysed by green mold
mold spore contaminates culture dish
left dish on bench top while on vacation
weather was unseasonably cold
particular strain of mold was a good penicillin producer
Structure of penicillin elucidated in X-ray crystal structure by Dorothy Hodgkin (Oxford)

30. Recently, the product of genetic engineering (e. g
Recently, the product of genetic engineering (e.g. recombinant insulin) through Recombinant DNA Technology.
It involves gene transfer to bacteria, production of the peptide product formed by expression of the transferred gene, and yielding the peptide product.

31. Finding a Lead compound???
1. Random screening
Disadvantage: Quite complex structures is extremely difficult to
synthesize , we have to design simpler analogues.
I- High throughput Screening (HTPS).
II- Virtual Screening.

32. I- High throughput Screening (HTPS).
Very rapid and sensitive method.
Can test a large number of compounds.
It is a biological method.

33. High-throughput screens (HTSs) are very rapid and sensitive in vitro screens that can be carried out robotically in or well titer plates on small (submicrograms) amount of the compounds.
1536- or well titer plates

34. II- Virtual Screening.
Virtual screening (in silico screening) is an interesting approach in lead discovery.
It involves the screening of chemical databases to identify compounds that are fitting and interacting with the receptor of study.
It is a computational screening.

35. A. The plant kingdom
A rich source of lead compounds (e.g. morphine, cocaine,
digitalis, quinine, tubocurarine, nicotine, muscarine and many
others). Recently, the anticancer agent Paclitaxel (Taxol)®, and
the antimalarial agent artemisinin have been separated from
the yew tree, and a chinese plant, respectively.
eg. Morphine from Papaver somniferum Quinine from Cinchona bark.

36. Paclitaxel
e.g. Artemisinin: antimalarial isolated from shrub, containing extremely unstable looking trioxane ring (no chemist would dream to synthesize)
Sildenafil the anti-impotence drug vasodilator in the penis more than in the heart

37. B. The Microbiological World
Bacteria have provided rich pickings for drugs and lead compounds e.g. Penicillins
Soil and water samples were collected from all around
the world, led to discovery of cephalosporins, tetracyclins,
aminoglycosides, rifamycins and chloramphenicol.
Fungal metabolite:
Asperlicin, isolated from Aspergillus alliaceus, antagonize
cholecystokinin hormone and used to control appetite, and treat
anxiety).
Lovastatin (lower cholesterol level).
Cyclosporins (immune suppressant in transplantation).

38. C. The Marine World
Coral and sponges have a wealth of biologically potent
chemicals, e.g. A potent antitumor agent.
Curacin A, is obtained from a marine cyanobacterium.

39. D. Animal Sources A potent analgesic compound called epibatidine was
obtained from the skin extract of the Ecuadorian
poison frog.

40. E. Venoms and toxins
From animals, plants, insects, and microorganisms.
e. g. Teprotide is a peptide isolated from the venom of the Brazilian
viper and was the lead compound for the development of the
antihypertensive agents Captopril and Cilazapril (ACE inhibitors).
Captopril

41. F. ENDOGENOUS COMPOUNDS
NATURAL LIGANDS FOR RECEPTORS
Agonist
Agonist
(Serotonin)

42. F- ENDOGENOUS COMPOUNDS (cont.)
NATURAL LIGANDS FOR RECEPTORS
Antagonist
Antagonist

43. F- ENDOGENOUS COMPOUNDS (cont.)
- NATURAL SUBSTRATES FOR ENZYMES
Enkephalins
Enkephalinase inhibitors
Peptides
Protease inhibitors

44. Lead compounds with activity –
Flow of Drug Discovery
Target screening – 1,250,000 compounds
Lead compounds with activity –
2,500 compounds
Clinical trials – 1 compound

45. SYNTHETIC COMPOUNDS SYNTHETIC COMPOUNDS
G-Lead Compounds from the Synthetic World
SYNTHETIC COMPOUNDS
SYNTHETIC COMPOUNDS
MOR008C.WAV

46. i- Screening synthetic banks
Chemicals or intermediates synthesized by the pharmaceutical companies or purchased from research groups for studying a new target.
e.g. INH is more active intermediate than the target structure isonicotinaldehyde thiosemicarbazone.

47. PRONTOSIL

48. SULFANILAMIDE

49. TNT

50. ii- COMBINATORIAL SYNTHESIS
Automated solid phase procedure aimed at producing as many different structures as possible in a short time as possible.
AUTOMATED SYNTHETIC MACHINES

51. Combinatorial chemistry
Is an approach that provides efficient synthesis of a large collection of molecules
Generates a wide diversity of compounds and reduces the cycle time for drug screening
An intentionally created collection of differing molecules which can be prepared either synthetically or biosynthetically

53. A1-B1
A2-B1
A3-B1
A1-B2
A2-B2
A3-B2
A1-B3
A2-B3
A3-B3

54. New compounds with improved biological activity
Compounds + biological activity
QSAR
New compounds with improved biological activity

55. 2. Clinical Observations of Side Effects of Drugs
An existing drug may have an undesirable side effect, which might be used as a lead compound based on its side effects.
e.g. 1. Sulphonamides are used as antibacterial agents possess
convulsive effect brought on by hypoglycemia, and has a
diuretic effect in large dose.
Structural modifications were made to the sulphonamide to
enhance both the hypoglycemic activity and the diuretic effect

57. e.g. 2. Enhancing the sedative side effect of promethazine (antihistamine), developed the neuroleptic agent chlorpromazine.
Sildenafil the anti-impotence drug vasodilator in the penis more than in the heart

58. Clinical Observations (cont.) e.g.3. Sildenafil (Viagra)
Developed for angina and hypertension by Pfizer
Lack of potency in Phase II trials sent the drug back to Phase I trials to determine highest tolerated dose.
Volunteers in second trial reported increased erectile function
Became first treatment for erectile dysfunction [see also: tadalafil (Cialis) and vardenafil HCl (Levitra).

59. 3. Drug Metabolites as Leads for Drug Discovery

60. Drug Metabolism Studies (cont.)
Terfenadine HCl (Seldane) caused arrhythmia in some patients also taking certain antifungals
Fexofenadine HCl (Allegra) is a metabolite of terfenadine that is also a non-sedating antihistamine and can be metabolized in presence of antifungals

61. 4. Rational Approaches
The key information that permits rational approaches to drug design is:
knowledge of the etiology of a given disease or at least the biochemical processes that are disturbed.
Try to find a proper method for inhibition of the life cycle of this organism (For example; enzyme inhibition).
Design of lead compound by computational and/or biological methods.
Examples of the rational approach are the discovery of the inhibitors of the angiotensin-converting enzyme.
Captopril

62. e.g. 2) the oral contraceptive 17 α-ethynyl estradiol
is prepared by analogy to 17 β-estradiol and it was
found to possess stronger activity and longer
duration.

63. e.g. 3) Serotonin the inflammation mediator was used as a lead for antiinflammatory agents, from which Indomethacin was developed.
Serotonin
Indomethacin

64. 5. Computer Aided Design
A detailed knowledge of a target binding site aids
the design of novel lead compounds intended to
bind with that target.
If enzymes or receptors can be crystallized, it is
possible to determine its structure and its binding
site by X-ray crystallography, molecular modeling
soft ware programs can then be used to study
the binding site and design molecules which will fit
and bind.

65. Very few lead compounds are ideal. Most are likely to have:
If the lead compound has useful biological activity. Why bother making analogues?
Very few lead compounds are ideal. Most are likely to have:
Low activity
Poor selectivity
Significant side effects
So optimization of the interaction between the drug and its target will allow higher activity and selectivity

66. DRUG DESIGN AND DEVELOPMENT Stages
1) Identify target disease
2) Identify drug target
3) Establish testing procedures
4) Find a lead compound
5) Structure Activity Relationships (SAR)
6) Identify a pharmacophore
7) Drug design- optimising target interactions
8) Drug design - optimising pharmacokinetic properties
9) Toxicological and safety tests
10) Chemical development and production
11) Patenting and regulatory affairs
12) Clinical trials

67. 1. TARGET DISEASE Priority for the Pharmaceutical Industry
Can the profits from marketing a new drug outweigh the cost of developing and testing that drug?
Questions to be addressed
Is the disease widespread?
(e.g. cardiovascular disease, ulcers, malaria)
Does the disease affect the first world?
(e.g. cardiovascular disease, ulcers)
Are there drugs already on the market?
If so, what are there advantages and disadvantages?
(e.g. side effects)
Can one identify a market advantage for a new therapy?

68. 2. DRUG TARGETS A) LIPIDS Cell Membrane Lipids B) PROTEINS
Receptors Enzymes Carrier Proteins Structural Proteins (tubulin)
C) NUCLEIC ACIDS
DNA RNA
D) CARBOHYDRATES
Cell surface carbohydrates Antigens and recognition molecules

69. Drug targets Drug Binding site Binding regions Binding groups
Intermolecular
bonds
Drug
Binding
site
Macromolecular target
Drug
Bound drug
Macromolecular target
Unbound drug

70. - Messenger binding Induced fit
Binding site is nearly the correct shape for the messenger
Binding alters the shape of the receptor (induced fit)
Altered receptor shape leads to further effects - signal transduction

71. Induced fit - Binding site alters shape to maximise intermolecular bonding
Phe
Ser O H
Asp
CO2
Phe
Ser O H
Asp
CO2
Induced
Fit
Intermolecular bonds not optimum length for maximum binding strength
Intermolecular bond lengths optimised

72. Overall process of receptor/messenger interaction
Signal transduction
Binding interactions must be:
- strong enough to hold the messenger sufficiently long for signal transduction to take place
- weak enough to allow the messenger to depart
Implies a fine balance
Drug design - designing molecules with stronger binding interactions results in drugs that block the binding site - antagonists

73. Agonists Agonist binds reversibly to the binding site
Similar intermolecular bonds formed as to natural messenger
Induced fit alters the shape of the receptor in the same way as the normal messenger
Receptor is activated
Agonists are often similar in structure to the natural messenger E
Agonist R E
Agonist R
Agonist R
Induced fit
Signal transduction

74. Competitive (reversible) antagonists
Antagonist binds reversibly to the binding site
Intermolecular bonds involved in binding
Different induced fit means receptor is not activated
No reaction takes place on antagonist
Level of antagonism depends on strength of antagonist binding and concentration
Messenger is blocked from the binding site
Increasing the messenger concentration reverses antagonism

75. Non competitive (irreversible) antagonistsOH OH X O X
Covalent Bond
Irreversible antagonism
Antagonist binds irreversibly to the binding site
Different induced fit means that the receptor is not activated
Covalent bond is formed between the drug and the receptor
Messenger is blocked from the binding site
Increasing messenger concentration does not reverse antagonism

76. Overall process of enzyme catalysis
E + P S E ES P E EP
Binding interactions must be;
- strong enough to hold the substrate sufficiently long for the reaction to occur
- weak enough to allow the product to depart
Implies a fine balance
Drug design - designing molecules with stronger binding interactions results in enzyme inhibitors which block the active site

77. Competitive (reversible) inhibitors
Inhibitor binds reversibly to the active site
Intermolecular bonds are involved in binding
No reaction takes place on the inhibitor
Inhibition depends on the strength of inhibitor binding and inhibitor concentration
Substrate is blocked from the active site
Increasing substrate concentration reverses inhibition
Inhibitor likely to be similar in structure to the substrate

78. Non competitive (irreversible) inhibitorsOH X OH X O
Covalent Bond
Irreversible inhibition
- Inhibitor binds irreversibly to the active site
- Covalent bond formed between the drug and the enzyme
- Substrate is blocked from the active site
- Increasing substrate concentration does not reverse inhibition
- Inhibitor likely to be similar in structure to the substrate

79. Non competitive (reversible) allosteric inhibitors
(open)
ENZYME
Enzyme
Induced
fit
Active site
unrecognisable
Active site
ACTIVE SITE
(open)
ENZYME
Enzyme
Allosteric
site
Allosteric
inhibitor
- Inhibitor binds reversibly to the allosteric site
- Intermolecular bonds are formed
- Induced fit alters the shape of the enzyme
- Active site is distorted and is not recognised by the substrate
- Increasing substrate concentration does not reverse inhibition
- Inhibitor is not similar in structure to the substrate

80. TARGET SELECTIVITY Between species Within the body
Antibacterial and antiviral agents
Identify targets which are unique to the invading pathogen
Identify targets which are shared but which are significantly different in structure
Within the body
Selectivity between different enzymes, receptors etc.
Selectivity between receptor types and subtypes
Selectivity between isozymes
Organ selectivity

81. 3. TESTING DRUGS
Tests are required in order to find lead compounds and for drug optimisation
Tests can be in vivo or in vitro
A combination of tests is often used in research programs

82. 3.1 in vivo Tests Carried out on live animals or humans
Measure an observed physiological effect
Measure a drug’s ability to interact with its target and its ability to reach that target
Can identify possible side effects
Rationalisation may be difficult due to the number of factors involved
Transgenic animals - genetically modified animals
Drug potency - concentration of drug required to produce 50% of the maximum possible effect
Therapeutic ratio/index - compares the dose level of a drug required to produce a desired effect in 50% of the test sample (ED50) versus the dose level that is lethal to 50% of the sample (LD50)

83. 3.2 in vitro Tests Tests not carried out on animals/humans
Target molecules (e.g. isolated enzymes or receptors) Cells (e.g. cloned cells) Tissues (e.g. muscle tissue) Organs Micro-organisms (for antibacterial agents)
More suitable for routine testing
Used in high throughput screening
Measure the interaction of a drug with the target but not the ability of the drug to reach the target
Results are easier to rationalise - less factors involved
Does not demonstrate a physiological or clinical effect
Does not identify possible side effects
Does not identify effective prodrugs

84. 3.2.1 Enzyme Inhibition Tests
Identify competitive or non competitive inhibition
Strength of inhibition measured as IC50
IC50 = concentration of inhibitor required to reduce enzyme activity by 50%
3.2.1 Enzyme Inhibition Tests

85. 3.2.2 Testing with Receptors
Not easy to isolate membrane bound receptors
Carried out on whole cells, tissue cultures, or isolated organs
Affinity - strength with which compounds bind to a receptor
Efficacy - measure of maximum biochemical effect resulting from binding of a compound to a receptor.
Potency - concentration of an agonist required to produce 50% of the maximum possible effect.

86. Dose = amount of drug administered to the patient
Dose Response Relationships
Dose = amount of drug administered to the patient
Response = effect in the body produced by the drug
Drug + Receptor  Drug-Receptor Complex 
Response

87. Log Drug Concentration [Molar]
100 3 4
Response 50 2 1
ED50
Log Drug Concentration [Molar]
KEY PARAMETERS
1. Dose required to produce any effect at all.
2. ED50 = effective dose to produce 50% response
3. Dose required to produce maximum effect
4. Dose that produces a toxic response.

88. Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy

89. Log Drug Concentration [Molar]
Potency vs Efficacy
Potency – how much drug is required to produce a certain effect.
100
Response 50 2 1
ED50
Log Drug Concentration [Molar]

91. Efficacy – how large an effect the drug produces.
Potency vs Efficacy
Efficacy – how large an effect the drug produces.
100
Response 50 2 1
ED50
Log Drug Concentration [Molar]