Drug Discovery & Development

PHC 311

Lec. 1

Reem Al-Wabli

Office no.; S67E-mail; ralwabli@ksu.edu.sa

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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.

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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))

References

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Credits Type

25 Midterm I 1

25 Midterm II 2

10 Term Activity* 4

40 Final exam 5

*Homework and Classroom Assignments and Discussion

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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

Topics to be covered

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• 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.

Medicinal Chemistry Folklore

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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.

Chemistry based disciplines

Organic ChemistryLife Sciences

Medicinal Chemistry

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Terms more or less synonymous with medicinal chemistry

• Pharmacochemistry• Molecular pharmacochemistry• Drug design

Medicinal Chemistry

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• 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).

Definition and Objectives

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• 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

Definition and Objectives (cont.)

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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

● 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.

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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

Classification Systems

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1) The origin of the drugDrugs 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.

Classification Systems (cont.)

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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.

Classification Systems (Cont.)

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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.

2) The mode of action (cont.)

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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 structureA great area for synthetic chemist to learn

Classification Systems (Cont.)

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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.

Practical Classifications

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1) Pharmacodynamic agents:

Affecting normal dynamic processes of the body.

2) Chemotherapeutic agents:

Drugs inhibiting the development of various kinds of infesting host.

3) Agents acting on metabolic diseases and on endocrine function.

4) Agents acting on the central nervous system:

Psychotropic and neurological drugs.

Common Medicinal Classifications

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1) Pharmacodynamic agents—affecting normal dynamic processes of the body

• Antiarrhythmics

• Antianginals

• Vasodilators

• Antihypertensives

• Antithrombotics

• Antiallergic drugs

Common Classification (Continued)

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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

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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

Common Classification (Continued)

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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

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Drug Design The goals and objectives of this course will emphasize a combination of f undamentals and applications of drug design and development. Special intonation will also be placed on the methods used by Medicinal Chemists to design new drugs to treat significant disease states, and by Pharmaceutical Chemists to develop, deliver and monitor eff ective therapeutic agents.

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Source of drugs

Plant 11.1

Semisynthesis9.5

Mineral 9.1

Animal 8.7

Microbial 6.4

Vaccine 4.3

Sera 2

Synthesis 48.9

Sources of Drugs

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Genesis of Drugs or How are New Drugs Discovered?

(Lead Structure Discovery)

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.

Lead compound: is Prototype compound that has the desired biological or pharmacological activity.

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

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Drug Discovery Without a Lead (Serendipity)

Penicillins: 1928 - Fleming

• 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

Bacteria lysed by green mold

Structure of penicillin elucidated in 1944 - X-ray crystal structure by Dorothy Hodgkin (Oxford)

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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.

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Finding a Lead compound???1. Random screeningDisadvantage: Quite complex structures is extremely difficult to synthesize , we have to design simpler analogues.

I- High throughput Screening (HTPS).

II- Virtual Screening.

Very rapid and sensitive method.

Can test a large number of compounds.

It is a biological method.

I- High throughput Screening (HTPS).

High-throughput screens (HTSs) are very rapid and sensitive in

vitro screens that can be carried out robotically in 1536- or 3456-

well titer plates on small (submicrograms) amount of the compounds.

1536- or 3456- well titer plates

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.

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A. The plant kingdomA rich source of lead compounds (e.g. morphine, cocaine, digitalis, quinine, tubocurarine, nicotine, muscarine and manyothers). 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.

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e.g. Artemisinin: antimalarial isolated from shrub, containing extremely unstable looking trioxane ring (no chemist would dream to synthesize)

Paclitaxel

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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).

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C. The Marine WorldCoral and sponges have a wealth of biologically potent

chemicals, e.g. A potent antitumor agent.

Curacin A, is obtained from a marine cyanobacterium.

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D. Animal SourcesA potent analgesic compound called epibatidine wasobtained from the skin extract of the Ecuadorian poison frog.

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E. Venoms and toxinsFrom 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

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F. ENDOGENOUS COMPOUNDS

NATURAL LIGANDS FOR RECEPTORS

HO

HO

ADRENALINE

HN

Me

OH

HO

HO

OH

SALBUTAMOL

HN

Agonist

NH2

NH

HO

5-HYDROXYTRYPTAMINE

NMe2

NH

SUMATRIPTAN

SMeHN

O OAgonist

)Serotonin(

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NATURAL LIGANDS FOR RECEPTORS

O NH

OH

PROPRANOLOL

AntagonistHO

HO

ADRENALINE

HN

Me

OH

HNN

Me

S

HN NHMe

CN

CIMETIDINE

HNN

NH2

HISTAMINEAntagonist

F- ENDOGENOUS COMPOUNDS (cont.)

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-NATURAL SUBSTRATES FOR ENZYMES

Enkephalins Enkephalinase inhibitors

Peptides Protease inhibitors

H2NN

HO

CO2HH

L-Phe-L-Pro

HN

NH

N

N

OCONH2

HO

H

H

OHH

H

H NH

O

SAQUINAVIR

F- ENDOGENOUS COMPOUNDS (cont.)

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Flow of Drug Discovery

Target screening – 1,250,000 compounds

Lead compounds with activity– 2,500 compounds

Clinical trials – 1 compound

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G-Lead Compounds from the Synthetic World

SYNTHETIC COMPOUNDSSYNTHETIC COMPOUNDS

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i- Screening synthetic banksChemicals 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.

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H2N S NH2

O

NN

NH2

O

PRONTOSIL

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S NH2

O

H2N

O

SULFANILAMIDE

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TNT

ONO2

ONO2

ONO2

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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

Generates a wide diversity of compounds and reduces the cycle time for drug screening

Combinatorial chemistry

Is an approach that provides efficient synthesis of a large collection of molecules

An intentionally created collection of differing molecules which can be prepared either synthetically or biosynthetically

A

B

C

D

A' B' C' D'

A'A B'A C'A D'A

A'B

A'C

A'D

B'B

B'C

B'D

C'B

C'C

C'D

D'B

D'C

D'D

E

E'

E'A

A'E B'E C'E D'E

E'B

E'C

E'D

E'E

*

O CHOOHC A2

CHOO2N

A1

CHO

NO2

A3

Br NHNH2

B1

NC NHNH2

B2

NNH2

H

HN

H2NB3

A1-B1 A2-B1 A3-B1

A1-B2 A2-B2 A3-B2

A1-B3 A2-B3 A3-B3

New compounds with improved biological activity

Compounds + biological activity

QSAR

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2. Clinical Observations of Side Effects of DrugsAn 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

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e.g. 2. Enhancing the sedative side effect of promethazine (antihistamine), developed the neuroleptic agent chlorpromazine.

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EtO

S

N

OO

NMe

N

HNN

N

O Me

C3H7

sildenafil(Viagra)

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).

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O N H

C H 3

O N H

C H 3

O H

O N H

C H 3

O C 2H 5

Acetanilid Acetaminophen Acetophenetidin

3. Drug Metabolites as Leads for Drug Discovery

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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

NPh

PhHO

HO

· HCl

terfenadine (Seldane)

NPh

PhHO

HOCO2H

· HCl

Fexofenadine

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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

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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.

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

NH

HO

NH2

N

H3CO

OH

CH3

O

Cl

O

Serotonin

Indomethacin

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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.

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If the lead compound has useful biological activity. Why bother making analogues?

• Very few lead compounds are ideal. Most are likely to have:

1. Low activity

2. Poor selectivity

3. Significant side effectsSo optimization of the interaction between the drug

and its target will allow higher activity and selectivity

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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 tests10) Chemical development and production11) Patenting and regulatory affairs12) Clinical trials

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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?

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2. DRUG TARGETS

A) LIPIDSCell Membrane Lipids

B) PROTEINS ReceptorsEnzymesCarrier ProteinsStructural Proteins (tubulin)

C) NUCLEIC ACIDS

DNARNA

D) CARBOHYDRATESCell surface carbohydratesAntigens and recognition molecules

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Macromolecular target

Drug

Unbound drug

Macromolecular target

Drug

Bound drug

Bindingsite

Drug

Binding site

Binding regions

Binding groups

Intermolecular bonds

Drug targets

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-Messenger binding

• 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

Messenger

Induced fit

M

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• Induced fit - Binding site alters shape to maximise intermolecular bonding

Intermolecular bonds not optimum length for maximum binding strength

Intermolecular bond lengths optimised

Phe

SerO

H

Asp

CO2 Induced Fit

Phe

Ser

OH

Asp

CO2

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Overall process of receptor/messenger interaction

M

M

ER

• 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

R

M

ER

Signal transduction

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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

Signal transduction

Agonist

R

Induced fit

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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

An

ER

M

An

R

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Non competitive (irreversible) antagonists

• 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

X

OH OH

X

O

Covalent Bond

Irreversible antagonism

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Overall process of enzyme catalysis

S

E

ES

P

E

EP

P

E

E + P

E

S

E + S

E

• 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

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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

I

EE

S

I

E

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Non competitive (irreversible) inhibitors

- 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

X

OH OH

X

O

Covalent Bond

Irreversible inhibition

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ACTIVE SITE) open(

ENZYMEEnzyme

Non competitive (reversible) allosteric inhibitors

- 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

Allostericsite

Active site

) open(ENZYMEEnzyme

Inducedfit

Active siteunrecognisable

Allostericinhibitor

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Between species

• 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

TARGET SELECTIVITY

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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

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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)

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• Tests not carried out on animals/humansTarget 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

3.2 in vitro Tests

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• 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

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• 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.

3.2.2 Testing with Receptors

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Dose = amount of drug administered to the patient

Response = effect in the body produced by the drug

Drug + Receptor Drug-Receptor Complex

Response

Dose Response Relationships

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Response

Log Drug Concentration [Molar]

0

100

50

ED50

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 effect4. Dose that produces a toxic response.

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1

2

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]

0

100

50

ED501

2

Potency vs Efficacy•Potency – how much drug is required to produce a certain effect.

Response

90

Analgesia

Dose

hydromorphone

morphine

codeine

aspirin

Relative Potency

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Log Drug Concentration [Molar]

0

100

50

ED501

2

Potency vs Efficacy

•Efficacy – how large an effect the drug produces.

Response

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Effectiveness, toxicity, lethality

• ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves

• TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect

• LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects

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Quantification of drug safety

Therapeutic Index = TD50 or LD50

ED50

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dose

Drug A

sleepdeath

100

50

0ED50 LD50

PercentResponding

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dose

Drug B

sleepdeath

100

50

0ED50 LD50

PercentResponding