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Drug Discovery & Development
PHC 311
Lec. 1
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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)
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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.
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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.
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Very rapid and sensitive method.
Can test a large number of compounds.
It is a biological method.
I- High throughput Screening (HTPS).
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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
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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
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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
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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
*
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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
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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
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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
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Log Drug Concentration [Molar]
0
100
50
ED501
2
Potency vs Efficacy•Potency – how much drug is required to produce a certain effect.
Response
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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