Introduction to Medicinal Chemistry 1431.pdf

8/12/2019 Introduction to Medicinal Chemistry 1431.pdf

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Introductionto Medicinal

Chemistry

Dr. Majdi Bakhaitan

Assistant professor medicinal chemistry

www.uqu.edu.sa/mmbakhaitan

[email protected]

www.uqumed1.pbworks.com

Medicinal chemistry is the design and

synthesis of novel drugs, based on anunderstanding of how they work at themolecular level. A useful drug must interact

with a molecular target in the body(Pharmacodynamics) and also be capable ofreaching that target (Pharmacokinetics).

G. Patrick
http://www.uqu.edu.sa/mmbakhaitanmailto:[email protected]:[email protected]://www.uqu.edu.sa/mmbakhaitan


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Medicinal chemistryconcerns the discovery, development,

identification, and the interpretation of the mode of action of

biologically active compounds at the molecular level.

IUPAC

Medicinal chemistryinvolves the isolation, characterization, and

synthesisof compounds that can be used in medicine for the

prevention, treatment, and cure of disease.

Burger

It provides thus, the chemical basisfor the interdisciplinary field of

therapeutics

BASED ON THE HOPE OF FINDING

BIOCHEMICAL RATIONALES FOR

DRUG DISCOVERY.

It is also called therapeutic chemistry,

pharmaceutical chemistry, and pharmaco-

chemistry

Finding the biochemical pathwaythroughwhich drugs exert their beneficial effects has

become a dominating activity of medicinal

chemist


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Pharmaceutical chemistry:

concerned primarily with modifications of

structures having known physiological or

pharmacological effect and with drug

analysis

Medicinal Chemist

A Medicinal Chemist is skilled in the field oforganic synthesis, molecular modeling and drugdesign. And should have a basic knowledge ofrelevant subjects such as biochemistry andPharmacology.

Drugs

Drugs are normally low molecular weight molecules thatinteract with macromolecular targets in the body to

produce a pharmacological effects. That effect may bebeneficial or harmful depending on the drug used andthe dose administered.


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is a chemical compound that haspharmacological or biologicalactivity and whose chemicalstructure is used as a starting pointfor chemical modifications in orderto improve potency, selectivity, orpharmacokinetic parameters

Aleadcompound

SOURCES OF LEAD COMPOUND


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10,000 COMPOUNDS

1,000 COMPOUNDS

10 COMPOUNDS

1COMPOUND

2-3Years

6-8Years

3-4Years

1Year

OngoingCOMPOUND DISCOVERY

SAFETY TESTING

PREPARED IND SUBMISSION

CLINICAL DEVELOPMENT:

- Metabolism & Pharmacokinetics

- Formulation Research

- Process Development

- Clinical Phase(I, II, III)

- Toxicology

DRUG

SUBMISSION

Drug Discovery and Development

The time from conception to approval of a new drug is

typically 12-15 years with estimated cost of $2000 M!!

10,000 COMPOUNDS

3-4Years


SAFETY TESTING

10,000 COMPOUNDS

1,000 COMPOUNDS

3-4Years

1Year


SAFETY TESTING


10,000 COMPOUNDS

1,000 COMPOUNDS

10 COMPOUNDS

6-8Years

3-4Years

1Year


SAFETY TESTING


CLINICAL DEVELOPMENT:

- Metabolism & Pharmacokinetics

- Formulation Research

- Process Development

- Clinical Phase(I, II, III)

- Toxicology


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hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh

hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh

Plant and microbial

natural products


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Isolated from Penicilliumcitrinum


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Sources of Drugs

1- Synthesis 50%A) Conventional synthesis of small molecule APIs:

-Classical synthetic chemistry Sequential synthesis ):takes plenty of time

Ex. starting from toluene, the synthesis of

procaine/procainamide

CH3

NH2

XN Et

Et

O

B) Combinatorial chemistry (CC) technology:It is usually followed by high throughput screening(HTS) / Ultrahigh

throughput screening(UHTS) and this has greatly reduced the time

needed for synthesis of compounds.

Procaine

O

O

N

NH2

CH3

2- Micro-organisms 12% ( e.g.Antibiotics)

3- Minerals 6% ( e.g.zinc)

4- Plants 25% ( e.g.cocaine)

5- Animals 6% ( e.g.serum)

6-Biotechnology: (e.g. for macromolecules).

N

CH3COOMe

H

O

OCocaine


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S

NH

NH

OO

S

NH2

OO

Cl

SNH

N

OO

NH2

S

NH2

OO

Existing Drugs

To enhance Existing side effect to be used in anotherfield of treatment.E.g.Antibacterial sulfonamide and tolbutamide orchlorothiazide .

Tolbutamide Suphanilamide Chlorthiazide

N

ONH

O

OCOOH

N COOHH

OHSH CH3

Existing DrugsExisting drugs may be useful as a bases for anotherdesign modification to retain and improve therapeutic

activity.E.g. The lead compound captopril is used to prepareenalapril which is more active and devoid of unwantedside effect

Captopril

Enalapril


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Serendipitous discoveries


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Endogenous neurotransmittersThe natural ligand of a target receptor has sometimes beenused as the lead compound.

The natural neurotransmitters adrenaline andnoradrenaline were the starting points for development ofadrenergic - agonist such as

NH

OH

OHH

OH

Salbutamol

NHROH

OH

OHH

Adrenaline


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The design of novel agents based on a knowledge of the targetbinding site

De NovoDrug Design

Procedure

Crystallise target protein with bound ligandAcquire structure by X-ray crystallographyDownload to computer for molecular modelling studiesIdentify the binding siteRemove the ligand in silicoIdentify potential binding regions in the binding siteDesign a lead compound to interact with the binding siteSynthesise the lead compound and test it for activityCrystallise the lead compound with the target protein andidentify the actual binding interactionsOptimise by structure-based drug design


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The design of novel agents based on a knowledge of the targetbinding site

De NovoDrug Design

ProcedureCrystallise target protein with bound ligandAcquire structure by X-ray crystallographyDownload to computer for molecular modelling studiesIdentify the binding siteRemove the ligand in silicoIdentify potential binding regions in the binding site

Design a lead compound to interact with the binding siteSynthesise the lead compound and test it for activityCrystallise the lead compound with the target protein andidentify the actual binding interactionsOptimise by structure-based drug design


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Proteomicsis the large-scale study of proteins, particularlytheir structures and functions. Proteins are vital parts ofliving organisms, as they are the main components of thephysiological metabolic pathways of cells. The term

"proteomics" was first coined in 1997to make an analogywith genomics, the study of the genes. The word "proteome"is a blend of "protein" and "genome", The proteome is theentire complement of proteins,including the modificationsmade to a particular set of proteins, produced by anorganism or system. This will vary with time and distinctrequirements, or stresses, that a cell or organism undergoes.


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High-throughput screening (HTS)is a method forscientific experimentation especially used in drugdiscovery and relevant to the fields of biology and

chemistry. Using robotics, data processing and controlsoftware, liquid handling devices, and sensitive detectors,High-Throughput Screening or HTS allows a researcher toquickly conduct millions of biochemical, genetic orpharmacological tests. Through this process one canrapidly identify active compounds, antibodies or genes

which modulate a particular biomolecular pathway. Theresults of these experiments provide starting points fordrug design and for understanding the interaction or roleof a particular biochemical process in biology.


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1. Cell Structure2. Cell Membrane

3. Drug targets4. Intermolecular bonding forces

4.1 Electrostatic or ionic bond4.2 Hydrogen bonds4.3 Van der Waals interactions4.4 Dipole-dipole interactions4.5 Ion-dipole interactions4.6 Induced dipole interactions

5. Desolvation penalties6. Hydrophobic interactions

Contents

Nucleus

1. Cell Structure

Cytoplasm

Plasma membrane

Phospholipid bilayer


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PolarHeadGroup

Hydrophobic Tails

2. Cell Membrane

PolarHeadGroup

Hydrophobic Tails

CHCH2 CH2

O O

O

P OO

O

CH2CH2NMe3

O O

Polar

HeadGroup

Hydrophobic Tails

CHCH2 CH2

O O

O

P

O

O

O

CH2CH2NMe3

O O

2. Cell Membrane


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2. Cell MembraneNotes:

The cell membrane ismade up of a

phospholipid bilayer

The hydrophobictails interact with

each other by van derWaals interactionsand are hidden fromthe aqueous media

The polar head groups interactwith water at the inner and

outer surfaces of themembrane

The cell membraneprovides a hydrophobicbarrier around the cell,

preventing the passage ofwater and polar molecules

Proteins arepresent, floating inthe cell membrane

(ion channels,receptors, enzymes

and transportproteins)

Lipids

Cell membrane lipids

Proteins

ReceptorsEnzymes

Transport proteinsStructural proteins

(tubulin)

Nucleic acids

DNARNA

Carbohydrates

Cell surface carbohydrates

Antigens and recognition molecules

3. Drug targets


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DRUG TARGETS:RECEPTORS

Patrick: An IntroductiontoMedicinalChemistry 4e

1. Structure and function of receptors

Globular proteins actingas a cells letter boxes

Located mostly inthe cell membrane

Receive messagesfrom chemical

messengerscoming from other

cells

Transmit a messageinto the cell leading

to a cellular effect

Different receptorsspecific for different

chemical messengers

Each cell has a range ofreceptors in the cell

membrane making it

responsive to differentchemical messengers


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Cell

Nerve


Messenger

Signal

Receptor

Nerve

NucleusCell

Response


Chemical Messengers

Neurotransmitters: Chemicals released from nerve endings whichtravel across a nerve synapse to bind with receptors on target cells,

such as muscle cells or another nerve. Usually short lived andresponsible for messages between individual cells

Hormones: Chemicals released from cells or glands and whichtravel some distance to bind with receptors on target cellsthroughout the body

Note: Chemical messengers switch on receptors withoutundergoing a reaction


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Nerve 1

Nerve 2Hormone

Bloodsupply

Neurotransmitters

Mechanism

Receptors contain a binding site (hollow or cleft on the receptorsurface) that is recognised by the chemical messenger

Binding of the messenger involves intermolecular bonds

Binding results in an induced fit of the receptor protein

Change in receptor shape results in a domino effect

Domino effect is known as Signal Transduction, leading to a chemicalsignal being received inside the cell

Chemical messenger does not enter the cell. It departs the receptorunchanged and is not permanently bound



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Mechanism


CellMembrane

Cell

Receptor

Messenger

message

Induced fit

Cell

Receptor

Messenger

Message

Cell

Messenger

Receptor

ENZYME

2. The Binding Site

A hydrophobic hollow or cleft on the receptor surface - equivalent to theactive site of an enzyme

Accepts and binds a chemical messenger

Contains amino acids which bind the messenger

No reaction or catalysis takes place

Binding siteBinding site


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3. Messenger Binding

Notes:

Binding site is nearly the correct shape for the messengerBinding alters the shape of the receptor (induced fit)Altered receptor shape leads to further effects - signal transduction

3.1 Introduction

Messenger

Induced fit

M


IonicH-bondingvan der Waals

3.2 Bonding forces

Example

Receptor

Binding site

vdwinteraction

ionicbond

H-bond

Phe

Ser

OH

Asp

CO2


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Induced fit - Binding site alters shape to maximise intermolecularbonding

3.2 Bonding forces

Intermolecular bonds notoptimum length for maximumbinding strength

Intermolecular bond lengthsoptimised

Phe

SerO

H

Asp

CO2 InducedFit

Phe

Ser

OH

Asp

CO2

4. Overall Process of Receptor/Messenger Interaction

M

M

ER

Notes:Binding interactions must be strong enough to hold the messengersufficiently long for signal transduction to take placeInteractions must be weak enough to allow the messenger to departImplies a fine balanceDesigning molecules with stronger binding interactions results in drugs thatblock the binding site - antagonists

R

M

ER

Signal transduction


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5. Receptor Superfamilies

ION CHANNEL RECEPTORS

G-PROTEIN COUPLED RECEPTORS

KINASE LINKED RECEPTORS

INTRACELLULAR RECEPTORS

MEMBRANEBOUND

RESPONSETIME

msecs

seconds

minutes

Major classes of drug receptors


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2004-2005

Signal transduction

1. enzyme linked(multiple actions)

2. ion channel linked(speedy)

3. G protein linked

(amplifier)

4. nuclear (gene) linked(long lasting)

4

6. Ion Channel Receptors

6.1 General principles

Receptor protein is part of an ion channel protein complex

Receptor binds a messenger leading to an induced fit

Ion channel is opened or closed

Ion channels are specific for specific ions (Na+, Ca2+, Cl-, K+)

Ions flow across cell membrane down concentration gradient

Polarises or depolarises nerve membranes

Activates or deactivates enzyme catalysed reactions within cell


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Hydrophilictunnel

Cellmembrane



Induced fitand opening

of ion channel

IONCHANNEL

(open)

Cell

Cellmembrane

MESSENGER

Ionchannel

Ionchannel

Cellmembrane

RECEPTORBINDING

SITE

IONCHANNEL(closed)

Cell

LockGate

Ionchannel

Ionchannel

Cellmembrane

Cellmembrane

MESSENGER




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Nicotinic receptor

Two ligand binding sitesmainly on a-subunits

a

a

g

d

b

Ion channel

2xa, b, g, dsubunits

Cellmembrane

a

ad

b

g

Bindingsites


6.2 Structure

Three ligand binding siteson a-subunits

a

a

b

b

a

Ion channel

3xa, 2xbsubunits

Cellmembrane

aa

abb

Binding

sites

Glycine receptor


6.2 Structure


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Structure of protein subunits (4-TM receptor subunits)

Extracellular loop

Intracellularloop

Variable loop

Neurotransmitter binding region

4 Transmembrane (TM) regions(hydrophobic)

H2N

CO2H

TM1 TM2 TM4TM3Cell

membrane


6.2 Structure

Detailed Structure of Ion Channel

Protein

subunits

Transmembraneregions

Note: TM2 of each protein subunit lines the central pore

TM4

TM4TM4

TM3

TM3

TM3

TM3

TM3 TM2

TM2

TM2TM2

TM2

TM1

TM1

TM1

TM1

TM1

TM4 TM4


6.2 Structure


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Five glycoprotein subunitstraversing cell membrane

MessengerReceptor

Inducedfit

Gating(ion channel

opens)

Cationic ion channels for K+, Na+, Ca2+(e.g. nicotinic) = excitatoryAnionic ion channels for Cl-(e.g. GABAA) = inhibitory

Binding site

Cellmembrane Cellmembrane


6.3 Gating

Chemical messenger binds to receptor binding siteInduced fit results in further conformational changes

TM2 segments rotate to open central pore


6.3 Gating

Closed

Transverse view

TM2TM2

TM2

TM2

TM2

Cellmembrane

TM2 TM2

Ion flow

Open

Transverse viewTM2

TM2

TM2

TM2

TM2


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Fast response measured in msec

Ideal for transmission between nerves

Binding of messenger leads directly to ion f lows across cell membrane

Ion flow = secondary effect (signal transduction)

Ion concentration within cell alters

Leads to variation in cell chemistry


6.3 Gating

7.1 General principlesReceptor binds a messenger leading to an induced fitOpens a binding site for a signal protein (G-protein)G-Protein binds, is destabilised then split

messenger

G-protein

split

7. G-ProteinCoupled Receptors

inducedfit

closed open
http://localhost/var/www/apps/downloads/Academic%20videos/G-Protein_Signaling.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/G-Protein_Signaling.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/G-Protein_Signaling.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/G-Protein_Signaling.flv


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G-Protein subunit activates membrane bound enzymeBinds to allosteric binding siteInduced fit results in opening of active siteIntracellular reaction catalysed

active site(closed)

active site(open)

Enzyme

Intracellularreaction

Enzyme

7. G-Protein Coupled Receptors


7.2 Structure - Single protein with 7 transmembrane regions

Transmembranehelix

C-Terminal chain

G-Proteinbinding region

Variableintracellular loop

Extracellularloops

Intracellular loops

N-Terminal chain

HO2C

NH2

VII VI V IV III II IMembrane



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7.3 Ligands


Monoamines: e.g. dopamine, histamine, noradrenaline, acetylcholine(muscarinic)

Nucleotides

Lipids

Hormones

Glutamate

Ca++

7.4 Ligand binding site - varies depending on receptor type

A) Monoamines: pocket in TM helices

B) Peptide hormones: top of TM helices + extracellular loops+N-terminal chain

C) Hormones: extracellular loops +N-terminal chain

D) Glutamate:N-terminal chain

Ligand

B DCA



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7.5 Bacteriorhodopsin & Rhodopsin Family

Rhodopsin = visual receptorMany common receptors belong to this same family

Implications for drug selectivity depending on similarity (evolution)

Membrane bound receptors difficult to crystallise

X-Ray structure of bacteriorhodopsin solved - bacterial protein similar torhodopsin

Bacteriorhodopsin structure used as template for other receptors

Construct model receptors based on template and amino acid sequence

Leads to model binding sites for drug design

Crystal structures for rhodopsin and b2-adrenergic receptors now solved -better templates


7.5 Bacteriorhodopsin & Rhodopsin Family

Common ancestor

EndothelinsOpsins, Rhodopsins

Tachykinins

Monoamines

alpha beta

H2 1

muscarinic

H12 4 15 3 2A 2B2C D1AD1B D5D4 D3 D2 3 2 1

Bradykinin,Angiotensin.Interleukin-8

Muscarinic Histamine -Adrenergic Dopaminergic -Adrenergic

Receptortypes

Receptorsub-types



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7.6 Receptor Types and Subtypes

Reflects differences in receptors which recognise the same ligand

Receptor Types Subtypes

Alpha (a)Beta (b)

a1, a2A, a2B, a2Cb1, b2, b3

Adrenergic

Muscarinic Nicotinic

Muscarinic M1-M5


Receptor types and subtypes not equally distributed amongst tissues.Target selectivity leads to tissue selectivity

Heart muscle

b1adrenergicreceptors

Fat cells

b3adrenergicreceptors

Bronchialmuscle

a1& b2adrenergicreceptors

GI-tract

a1 a2 & b2adrenergicreceptors

Note


7.6 Receptor Types and Subtypes


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8. Tyrosine Kinase Linked Receptors

Bifunctional receptor / enzyme

Activated by hormones

Overexpression can result in cancer


Protein serves dual role - receptor plus enzyme

Receptor binds messenger leading to an induced fit

Protein changes shape and opens active site

Reaction catalysed within cell

Overexpression related to several cancers

closed

messenger

inducedfit

active siteopen

intracellular reaction

closed

messenger



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8.2 Structure

NH2

CO2H

Cell membrane

Catalytic binding region(closed in resting state)

Ligand binding regionExtracellular

N-terminalchain

IntracellularC-terminalchain

Hydrophilictransmembraneregion (a-helix)


8.3 Reaction catalysed by Tyrosine Kinase

N C

O

Protein Protein

OH

Tyrosineresidue

Tyrosinekinase

Mg++

ATP ADP

N C

O

Protein Protein

O

Phosphorylatedtyrosineresidue

P



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8.4 Epidermal growth factor receptor (EGF- R)

Inactive EGF-Rmonomers

Cellmembrane

Binding site for EGF

EGF - protein hormone - bivalent ligand

Active site of tyrosine kinase

Induced fitopens tyrosine kinaseactive sites

Ligand bindingand dimerisation

OH

OHOH

HO

Phosphorylation

ATP ADP

OP

OPOPPO

EGF


Notes

Active site on one half of dimer catalyses phosphorylation of Tyr residueson other half

Dimerisation of receptor is crucial

Phosphorylated regions act as binding sites for further proteins andenzymes

Results in activation of signalling proteins and enzymes

Message carried into cell

8.4 Epidermal growth factor receptor (EGF- R)

http://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/TK%20Receptor%20Animation.flv


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8.5 Insulin receptor (tetrameric complex)

Insulin

Cellmembrane

Insulin binding site

Kinase active site

OP

Phosphorylation

ATP ADPOP

OPPO

Kinase active siteopened by induced fit


OHOHOH

HO

8.6 Growth hormone receptor

Tetrameric complex constructed in presence of growth hormone

Growth hormone binding site

Kinase active site

Kinase active siteopened by induced fit

GH

OHOH

OHHO

kinases

GH receptors(no kinase activity)

GH binding

&dimerisation

OPOPOP

PO

ATP ADP

Activation andphosphorylation

OH

Bindingof kinases

OHOHHO



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9. Intracellular Receptors

Chemical messengers must cross cell membrane

Chemical messengers must be hydrophobic

Example - steroids and steroid receptors

9. Intracellular Receptors9.1 Structure

Zinc

Zinc fingers contain Cys residues (SH)Allow S-Zn interactions

CO2H

H2N

DNA binding region(zinc fingers)

Steroidbinding region


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Cellmembrane

9. Intracellular Receptors9.2 Mechanism

1. Messenger crosses membrane2. Binds to receptor3. Receptor dimerisation

4. Binds co-activator protein

5. Complex binds to DNA6. Transcription switched on or off

7. Protein synthesis activated or inhibit

Messenger

Receptor

Receptor-ligandcomplex

Dimerisation

Co-activatorprotein

DNA

9. Intracellular Receptors9.3 Oestrogen receptor

Oestradiol

H12

Oestrogenreceptor

Bindingsite

AF-2regions

Dimerisation &exposure of

AF-2 regions

Coactivator

Nucleartranscription

factor

Coactivator

DNA

Transcription


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Notes

3. Drug targets

Drug targets are large molecules - macromolecules

Drugs are generally much smaller than their targets

Drugs interact with their targets by binding to binding sites

Binding sites are typically hydrophobic hollows or clefts on

the surface of macromolecules

Binding interactions typically involve intermolecular bonds

Most drugs are in equilibrium between being bound and

unbound to their target

Functional groups on the drug are involved in binding

interactions and are called binding groups

Specific regions within the binding site that are involved in

binding interactions are called binding regions

Macromolecular target

Drug

Bound drug

Induced fitMacromolecular target

Drug

Unbound drug

Binding

site

Drug

Binding site

Binding

regions

Binding

groups

Intermolecularbonds

3. Drug targets


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3. Drug targets

Notes

Binding interactions usually result in an induced fit wherethe binding site changes shape to accommodate the drug

The induced fit may also alter the overall shape of the drugtarget

Important to the pharmacological effect of the drug

4. Intermolecular bonding forces4.1 Electrostatic or ionic bond

Strongest of the intermolecular bonds (20-40 kJ mol-1)

Takes place between groups of opposite charge

The strength of the ionic interaction is inversely proportional to the

distance between the two charged groups

Stronger interactions occur in hydrophobic environments

The strength of interaction drops off less rapidly with distance than

with other forms of intermolecular interactions

Ionic bonds are the most important initial interactions as a drug enters

the binding site

Drug

O

O H3N Target

Drug NH3Target

O

O


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4. Intermolecular bonding forces4.2 Hydrogen bonds

X H

Drug

Y Target

Drug XTarget

HYd+d+

d- d-d--

HBD HBA HBA HBD

Vary in strength

Weaker than electrostatic interactions but stronger than van der Waalsinteractions

A hydrogen bond takes place between an electron deficient hydrogen andan electron rich heteroatom (N or O)

The electron deficient hydrogen is usually attached to a heteroatom (O orN)

The electron deficient hydrogen is called a hydrogen bond donor

The electron rich heteroatom is called a hydrogen bond acceptor


YX H YX H

Hybridisedorbital

Hybridisedorbital

1sorbital

HBAHBD

The interaction involves orbitals and is directional

Optimum orientation is where the X-H bond points

directly to the lone pair on Y such that the angle between X,

H and Y is 180o


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Examples of strong hydrogen bond acceptors

- carboxylate ion, phosphate ion, tertiary amine

Examples of moderate hydrogen bond acceptors

- carboxylic acid, amide oxygen, ketone, ester, ether, alcohol

Examples of poor hydrogen bond acceptors

- sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic

amine

Example of good hydrogen bond donors

- alkylammonium ion

4. Intermolecular bonding forces4.3 Van der Waals interactions

Binding site

DRUG

d- d+

Very weak interactions (2-4 kJ mol-1)

Occur between hydrophobic regions of the drug and the target

Transient areas of high and low electron densities cause

temporary dipolesInteractions drop off rapidly with distance

Drug must be close to the binding region for interactions to occur

The overall contribution of van der Waals interactions can be

crucial to binding

d+ d-

Hydrophobic regions

Transient dipole on drug+ d-van der Waals interaction


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4. Intermolecular bonding forces4.4 Dipole-dipole interactions

Can occur if the drug and the binding site have dipole

moments

Dipoles align with each other as the drug enters the binding

site

Dipole alignment orientates the molecule in the binding site

Orientation is beneficial if other binding groups are

positioned correctly with respect to the corresponding

binding regions

Orientation is detrimental if the binding groups are not

positioned correctly

The strength of the interaction decreases with distance

more quickly than with electrostatic interactions, but less

quickly than with van der Waals interactions

Binding site

Localiseddipole moment

Dipole moment

RC

R

O

dd-

Binding site

R

CR O

4.4 Dipole-dipole interactions

4. Intermolecular bonding forces


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4.5 Ion-dipole interactionsOccur where the charge on one molecule interacts with the dipole moment ofanotherStronger than a dipole-dipole interactionStrength of interaction falls off less rapidly with distance than for a dipole-dipole interaction

C

O

O

Binding site

dd-

R

C

R O

H3N

Binding site

dd-

R

CR O


4.6 Induced dipole interactionsOccur where the charge on one molecule induces a dipole on anotherOccur between a quaternary ammonium ion and an aromatic ring

Binding site

R NR3d-

d


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Unstructured waterIncrease in entropy

DrugDRUG

Structured water layerround hydrophobic regions

Hydrophobicregions

WaterBinding site Binding site

DrugDRUG

Binding

6. Hydrophobic interactions

Hydrophobic regions of a drug and its target are not solvatedWater molecules interact with each other and form an ordered

layer next to hydrophobic regions - negative entropy

Interactions between the hydrophobic regions of a drug and its

target free up the ordered water molecules

Results in an increase in entropy

Beneficial to binding energy

Covalent bonds would be very tight and practically irreversible.Since by definition the drug-receptor interaction is reversible,

covalent bond formation is rather rare except in a rather toxicsituation. Even though some classes act through covalentbonding such as proton pump inhibitors (omeprazol class), someantibiotics (Penicillins) and poisons such as organic phosphates.


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RC

R

O

OH

HH H

O

H

H

O

H

H

O

OH

Binding site

Desolvation - Energy penalty Binding - Energy gain

OH

RC

R

O

Binding site

RC

R

O

OH

Binding site

5. Desolvation penalties

Polar regions of a drug and its target are solvated prior tointeraction

Desolvation is necessary and requires energy

The energy gained by drug-target interactions must be greater

than the energy required for desolvation

RECEPTORS ASDRUG TARGETS



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An Agonist: is a substance that interacts with a specific

cellular constituent, the receptor, and elicits an observable

Biological response. It may be endogenous or exogenous

substance.

Partial agonists: acts on the same receptor as agonists ,however, regardless of its dose it cannot produce the samemaximal biological response as a full agonist

Definitions of Classical Binding Terms for Drug-Receptor Interactions

139

Intrinsic activity: is a proportionality constant ofthe ability of the agonist to activate the receptor as

compared to the maximally active compound inthe series being studied.

An antagonist: Inhibits the effect of an agonist buthas no biological activity of its own. It maycompete on the same receptor site that the agonistoccupies or it may act on allosteric site.

Definitions of Classical Binding Terms for Drug-Receptor

Interactions

140


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Interactions

An Inverse agonistnegative antagonist: it acts on thesame receptor of the agonist yet produces an inverseeffect. (e.g. Clozapine inverse agonist on 5-HT(2c) asantipsychotic)

The activity of inverse agonist is manifested in case ofpresence of base-line activity of the receptor without aligand.


Interactions

Affinity: is the ability of a drug to combine with a

receptor; it is proportional to the binding equilibriumconstant KD. A ligand of low affinity requires a higherconcentration to produce the same effect. Bothagonists and antagonists have affinity to the receptor.


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Interactions

Efficacy: Is a measure of the biochemical orphysiological effect which results, following thebinding of a drug to its target. Efficacy is ameasure of the maximum effect the drug canproduce

Potency: refers to the dose of a drug required toproduce a specific effect of given magnitude(usually 50% of the maximum effect) as comparedto a standard reference. Potency is dependentupon both affinity and efficacy


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2004-2005

dose response curves-2

effect = a [DR] = Emax * [D]/([D]+EC50)

a

% occupancy

Concept: spare

receptors

6

2004-2005

Analgesia

Dose

hydromorphone

morphine

codeine

aspirin

Relative Potency


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2004-2005

Agonists and antagonists

agonist has affinity plus intrinsic activity

antagonist has affinity but no intrinsic activity

partial agonist has affinity and less intrinsic activity

competitive antagonists can be overcome

10

2004-2005

Response

Dose

Full agonist

Partial agonist

Agonist Dose Response Curves


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2004-2005

ec veness, ox c y,

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 populationmanifests a given toxic effect

LD50 - Median Toxic Dose 50 - dose which

kills 50 percent of the subjects

2004-2005

Quantification of drug safety

Therapeutic Index =TD50 or LD50

ED50


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2004-2005

The therapeutic index The higher theTIthe better the drug.

TIsvary from: 1.0 (some cancer drugs)

to: >1000 (penicillin)

Drugs acting on the same receptor or enzyme system

often have the same TI: (eg 50 mg of

hydrochlorothiazide about the same as 2.5 mg of

indapamide)

9

2004-2005

dose

Drug A

sleepdeath

100

50

0ED50 LD50

Percent

Responding


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2004-2005

dose

Drug B

sleepdeath

100

50

0ED50 LD50

Percent

Responding

2004-2005

The therapeutic index

The higher the TI the better the drug.

TIs vary from: 1.0 (some cancer drugs)

to: >1000 (penicillin)

Drugs acting on the same receptor or enzyme system

often have the same TI: (eg 50 mg of

hydrochlorothiazide about the same as 2.5 mg of

indapamide)

9

2004-2005

Summary

most drugs act through receptors

there are 4 common signal transduction methods

the interaction between drug and receptor can be described

mathematically and graphically

agonists have both affinity(kd) and intrinsic activity (a)

antagonists have affinity only

antagonists can be competitive (change kd) or

non-competitive (change a) when mixed with agonists

agonists desensitize receptors.

antagonists sensitize receptors.

12


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Notes:Most receptors are located in the cell membraneReceptors are activated by chemical messengers (neurotransmittersorhormones)

1. Receptor function

CellMembrane

Cell

Receptor

Messenger

message

Induced fit

Cell

Receptor

Messenger

Message

Cell

Messenger

Receptor

Receptors contain a binding site (hollow or cleft in the receptorsurface) that is recognised by the chemical messenger

Binding of the messenger involves intermolecular bonds

Binding results in an induced fit of the receptor protein

Change in receptor shape results in a domino effect

Domino effect is known as signal transduction, leading to achemical signal being received inside the cell

Chemical messenger does not enter the cell. It departs thereceptor unchanged and is not permanently bound

1. Receptor function


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ENZYME

2. The Binding Site

A hydrophobic hollow or cleft on the receptor surface - equivalent to the activesite of an enzyme

Accepts and binds a chemical messenger

Contains amino acids which bind the messenger

No reaction or catalysis takes place

Binding siteBinding site


Notes:Binding site is nearly the correct shape for the messengerBinding alters the shape of the receptor (induced fit)Altered receptor shape leads to further effects - signal transduction

3.1 Introduction

Messenger

Induced fit

M


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IonicH-bondingvan der Waals

3.2 Bonding forces

Example

Receptor

Binding site

vdwinteraction

ionic

bond

H-bond

Phe

Ser

OH

Asp

CO2

3. Substrate Binding

Induced fit - Binding site alters shape to maximise intermolecularbonding

3.2 Bonding forces

Intermolecular bonds notoptimum length for maximum

binding strength

Intermolecular bond lengthsoptimised

Phe

SerO

H

Asp

CO2 InducedFit

Phe

Ser

OH

Asp

CO2


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M

M

ER

Notes:Binding interactions must be strong enough to hold the messenger

sufficiently long for signal transduction to take placeInteractions must be weak enough to allow the messenger to departImplies a fine balance of binding interactionsMessengers tend to bind and depart quickly

R

M

ER

Signal transduction


M

M

ER R

M

ER

Signal transduction

Notes on drug design:Agonists are drugs designed to mimic the natural messengerAgonists should bind and leave quickly - number of binding interactionsis importantAntagonists are drugs designed to block the natural messengerAntagonists tend to have stronger and/or more binding interactions,

resulting in a different induced fit such that the receptor is not activated.


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5. Design of Agonists5.1 Introduction

Agonists mimic the natural messenger of a receptorAgonists bind reversibly to the binding site and produce the same induced fitas the natural messenger - receptor is activatedSimilar intermolecular bonds formed as with natural messengerAgonists are often similar in structure to the natural messenger

E

Agonist

R E

Agonist

R

Signal transduction

Agonist

R

Induced fit

The discovery of pharmacological agents by modernpharmaceutical companies and universities ofteninvolves the use of receptorligand bindingtechniques.Following the synthesis of a series of new chemically

related compounds, which may constitute hundreds tothousands of compounds, thedetermination of thedesired biological activity was once a rather dauntingtask. Before the advent of receptorligand bindingtechniques, the initial screeningof these compoundsinvolved individually injecting each agent intoexperimental animals or incubating each agent withisolated tissues (e.g., intestine, heart, and skeletalmuscle), which are techniques that require a largeinvestment of resources, including personnel, time,animals, and money.


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Today, receptorligand binding techniques are used to narrow largenumbers of compounds down to those that display the greatest affinityfor a receptor, thereby significantly decreasing the time and costassociated with identifying lead compounds.

One danger associated with such an initial screening approach,however, is thefailure to recognize potentially useful compounds thatmight require biotransformation before exerting a biological effect,such as a pro-drug. Additionally, itshould be remembered that ligandbinding based on the affinity of a drug for a receptor does notdifferentiate agonists from antagonists. Despite these potential pitfallsassociated with receptorligand binding techniques, modern drugdiscovery relies heavily on these approaches.

5.2 Requirements

The agonist must have the correct binding groups

The binding groups must be correctly positioned tointeract with complementary binding regions

The drug must have the correct shape to fit the bindingsite

5. Design of Agonists


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5.3 Example of a hypothetical messenger and receptor

van der Waalsbinding regionH-bond

binding regionIonic binding region

Binding groups

Neurotransmitter

OO2C

H

Binding site

Receptor

NH2Me

OHH


O

NH2M e

H

HO

O2

C

H

Binding site

Receptor

O

NH2M e

H

HO

O2CH

Binding site

Receptor

INDUCEDFIT


5.3 Example of a hypothetical messenger and receptor

Induced fit allows stronger bindinginteractions


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Hypotheticalneurotransmitter

HONH2Me

H

Notes:Identify important binding interactions in natural messengerAgonists are designed to have functional groups capable of same interactionsUsually require same number of interactions


5.4 Correct binding groups

H-bondinggroup

van der Waals-bondinggroup

Ionicbindinggroup

H2NNH2Me

HNHMe

HO HONH2Me

HH

HMe

Possible agonists with similar binding groups

OO

2C

H

Binding site

Receptor

OO

2C

H

Binding site

Receptor

HCH2Me

H

Structure II has 2 of the 3 requiredbinding groups - weak activity

HNH2Me

H


5.4 Correct binding groups

I

H

CH2Me

H

II

HNH2Me

H

Structure I has one weak bindinggroup - negligible activity


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NotesBinding groups must be positioned such that they can interact withcomplementary binding regions at the same timeExample has three binding groups, but only two can bindsimultaneouslyExample will have poor activity

H

NH2

M e

OH

H

OO

2C

H

Binding site

2 Interactions only

H

NH2M e

H

OH

No interaction


5.5 Correct position of binding groups

NotesOne enantiomer of a chiral drug normally binds more effectively than thotherDifferent enantiomers likely to have different biological properties

OO

2C

H

Binding site

3 interactions

O

NH2Me

H

HO

O2

C

H

Binding site

2 interactions

OH

NH2Me

H

ONH2M e

H

H

OM eH2N

H

H

Mirror


5.5 Correct position of binding groups

Enantiomers of achiral molecule


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O

NH

2

H

H

Me

CH3

NotesAgonist must have correct size and shape to fit binding siteGroups preventing access are called steric shields or steric blocks

No Fit

O

O2

C

H

Binding site


5.6 Size and shape

C H3

Steric block

Me

Steric block

Agents which enhance receptor activity by binding to an allosteric binding siterather than the messenger binding site

Example

MeHN

CF3

Cinacalcet

Allosteric modulator for a G-protein coupledreceptor called the calcium-sensing receptor

Used to treat thyroid problems

6. Allosteric modulators

ExampleBenzodiazepines target the allosteric binding site of the GABAAreceptor


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7. Reversible Antagonists

Notes:Antagonist binds reversibly to the binding siteIntermolecular bonds involved in bindingDifferent induced fit means receptor is not activatedThe antagonist does not undergo any reaction

Level of antagonism depends on strength of antagonist binding andconcentrationMessenger is blocked from the binding siteIncreasing the messenger concentration reverses antagonism

An

ER

M

An

R

8. Design of Antagonists

Antagonists bind to the binding site but fail to produce the correct induced fit -receptor is not activatedNormal messenger is blocked from binding

O N

H

H

M e

H

H

OO

2C

H

Binding site

Perfect Fit(No change in shape)


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Antagonists can form binding interactions with binding regions in the bindingsite not used by the natural messenger

OHO

2C

Receptor binding site

Extra binding regions

O

O

Asp

-

HO


Antagonists can form binding interactions with extra binding regionsneighbouring the binding site for the natural messenger

Extra hydrophobicbinding region

Hydrophobicbinding region

Ionic bindingregion

H-bondbinding region

Hypotheticalneurotransmitter

NH2Me

HO

H


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Hydrophobicregion

O

O

Asp

-

HO


Induced fit resulting from binding of the normal messenger

NH2Me

HO

H

Hydrophobicregion

O

O

Asp

HO

-

NH2Me

HO

HInduced fit

Hydrophobicregion

O

O

Asp

HO

Hydrophobicregion

HO

Initial binding

-


Different induced fit resulting from extra binding interaction

NHMe

HO

H

Hydrophobicregion

O

O

Asp

HO

Different induced fit

-NHMe

HO

H


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9. Irreversible Antagonists

NotesAntagonist binds irreversibly to the binding siteDifferent induced fit means that the receptor is not activatedCovalent bond is formed between the drug and the receptorMessenger is blocked from the binding siteIncreasing messenger concentration does not reverse antagonismOften used to label receptors

X

OH OH

X

O

Covalent Bond

Irreversible antagonism

1

Nu

Nu

Receptor

Propylbenzilylcholine mustard

Cl

Cl

Agonistbinding site

Antagonistbinding site

C l

C l

HOO

O

NCl

Cl

9. Irreversible Antagonists

Nu

Nu

Receptor

2Irreversiblebinding


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10. Allosteric Antagonists

Notes:Antagonist binds reversibly to an allosteric binding siteIntermolecular bonds formed between antagonist and binding siteInduced fit alters the shape of the receptorBinding site is distorted and is not recognised by the messengerIncreasing messenger concentration does not reverse antagonism

ACTIVE SITE(open)

ENZYMEReceptor

Allostericbinding site

Binding site

(open)ENZYMEReceptor

Inducedfit

Binding site

unrecognisable

Antagonist

11. Antagonists by the Umbrella Effect

Notes:Antagonist binds reversibly to a neighbouring binding siteIntermolecular bonds formed between antagonist and binding siteAntagonist overlaps the messenger binding siteMessenger is blocked from the binding site

Antagonist

Binding sitefor antagonist

Binding sitefor messenger

messenger

Receptor Receptor


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12. Partial Agonists

Agents which act as agonists but produce a weaker effectPartialagonist Slight shift

Partial openingof an ion channel

Receptor

OO 2C

H

1

NH M e

O

H

H H

Receptor

O

O 2C

2

NH M e

O

H

H

Possible explanations

Agent binds but does notproduce the ideal

induced fit formaximum effect

Agent binds to binding site in twodifferent modes, one where theagent acts as an agonist and onewhere it acts as an antagonist

Agent binds as anagonist to one receptor

subtype but as anantagonist to another

receptor subtype

13. Inverse Agonists

Bind to receptor binding sites with a differentinduced fit from the normal messenger

Receptor is not activated

Normal messenger is blocked from binding tothe binding site

Propertiesshared with

antagonists

Block any inherent activity related to the receptor(e.g. GABA receptor)

Inherent activity = level of activity present in theabsence of a chemical messenger

Receptors are in an equilibrium betweenconstitutionally active and inactive forms

Propertiesnot shared

withantagonists


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Was developed on the basis of thekinetics of competitive and allostericinhibition as well as throughinterpretation of the results of directbinding experiments.

It postulates that a receptor, regardlessof the presence or absence of a ligand,exists in two distinct states: the R(relaxed, active or on) and T (Tense,inactive or off) states, which are inequilibrium with each other.

Thetwo-state

receptormodel

Molecular-level conceptual models of receptors

188

has a high affinity for the R

state and will shift theequilibrium to the right, Anantagonist (Inhibitor, I) willprefer the T state and willstabilize the TI complex.Partial agonists have aboutequal affinity for both forms ofthe receptor..

Anagonist(Drug,

D)

Molecular-level conceptual models of receptors

189


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14. Explanation of how drugs affect receptor equilibri A) Resting state

B) Addition of agonist

C) Addition of antagonist

D) Addition of inverse agonist

E) Addition of partial agonist

Inactive conformations Active conformation

Agonist binding site

15. Desensitization and Sensitization

DesensitizationReceptors become desensititized on long term exposure to agonistsProlonged binding of agonist leads to phosphorylation of receptorPhosphorylated receptor changes shape and is inactivatedDephosphorylation occurs once agonist departs

Receptor

O O2C

1

H Ion channel(closed)

AgonistNH3
http://localhost/var/www/apps/downloads/Academic%20videos/Opioid%20Tolerance.flvhttp://localhost/var/www/apps/downloads/Academic%20videos/Opioid%20Tolerance.flv


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Receptor

O

H

AgonistNH3

O2C


Desensitization

Receptors become desensititized on long term exposure toagonistsProlonged binding of agonist leads to phosphorylation ofreceptorPhosphorylated receptor changes shape and is inactivatedDephosphorylation occurs once agonist departs

Induced fit alters protein shapeOpens ion channel

Receptor

O

H

AgonistNH3

O2C


DesensitizationReceptors become desensititized on long term exposure to agonistsProlonged binding of agonist leads to phosphorylation of receptorPhosphorylated receptor changes shape and is inactivatedDephosphorylation occurs once agonist departs


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Receptor

O

H

AgonistP

O2C

NH3


Receptors become desensititized on long term exposure toagonists

Prolonged binding of agonist leads to phosphorylation ofreceptor

Phosphorylated receptor changes shape and is inactivated Dephosphorylation occurs once agonist departs

Desensitization

Phosphorylation alters shapeIon channel closesDesensitization


Sensitization

Receptors become sensititized on longterm exposure to antagonists

Cell synthesises more receptors tocompensate for blocked receptors

Cells become more sensitive to natural

messenger


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15. Desensitization and SensitizationSensitization

Antagonist

Neurotransmitter

Normal response

Receptor

synthesis

No response

Response

Stop

antagonistExcess response No response

Increaseantagonist

Tolerance

Receptor

synthesis

Sensitization

Dependence

No response

No response

PHARMACOPHORES



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DRUG DESIGN AND DEVELOPMENT

Stages1) 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

6. PHARMACOPHORE (Part Of the pharmacodynamic phase)

Defines the important groups involved in binding

Defines the relative positions of the binding groups

Need to know the active conformation

Important to drug design

Important to drug discovery


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6.1 Structural (2D) Pharmacophore

Defines minimum skeleton connecting important binding groups

O

NMe

HO

HO

MORPHINE


101/230


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N

HO

ANALGESIC PHARMACOPHORE FOR OPIOIDS

MORPHINE

O

NMe

HO

HO

NMe

HO

LEVORPHANOL

NMe

HO

METAZOCINECH3

H3C


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MORPHINE

O

NMe

HO

HO

NMe

HO

LEVORPHANOL

NMe

HO

METAZOCINE

CH3

H3C

6.2 3D Pharmacophore

Defines relative positions in space of important binding groups

Example

N

HO

HO

N

x

x


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O

NMe

HO

HO

MORPHINE

IMPORTANT GROUPS FOR ACTIVITY

O

NMe

HO

HO


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O

N

Ar


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O

N

Ar

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

Note:Defines relative positions in space of the important binding interactions whichare required for activity

Hydrogen bonding acceptorHydrogen bonding donor

van der Waals interactionIonic interaction

6.3 Generalised Bonding Type Pharmacophore


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O

N

Ar

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

3D Pharmacophore

HBA

Ionic

vdW

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

Bonding typepharmacophore


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HO NH2 HO

NH2

HO HO

I II

HO NH2 HO

NH2

HO HO

6.4 The Active Conformation

The conformation adopted by a drug when it bind to its targetIdentification of the active conformation is required in order toidentify the 3D pharmacophoreConformational analysis identifies possible conformations and theirstabilitiesConformational analysis is difficult for flexible molecules with largenumbers of conformationsEasier to compare activities of rigid analogues

Locked bonds

NH2HO

HO

Dopamine

Rotatablebonds

6.5 Pharmacophores from Target Binding Sites

H-bonddonor oracceptor

aromaticcenter

basic orpositivecenter

H-bond

donor oracceptor

aromaticcenter

basic orpositivecenter

Pharmacophore

OH

CO2

ASP

SER

PHE

Bindingsite


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6.6 Pharmacophore Triangles

HO

NH2

HO

Pharmacophore triangles for dopamine

HO

NH2

HO

HO

NH2

HO

ArAr

Basic

HBD/HBA

HBD/HBA

OPTIMIZING TARGET INTERACTIONS



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PHARMACOKINETICS


1. PHARMACOKINETICS

NotesFactors affecting whether a drug will reach its target siteActive drugs in vitromay be inactive in vivoThe most potent drug at its target site may be useless clinically

Drug design should consider binding interactions and pharmacokineticssimultaneously

Factors to consider(ADME)Drug AbsorptionDrug DistributionDrug MetabolismDrug Excretion


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2. DRUG ABSORPTION

Exceptions

Small polar molecules (MW


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein


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CellMembrane

Cell

RECEPTORCell

Membrane

TransportProtein

2. DRUG ABSORPTION

Exceptions

Drug Pinocytosis

Drug releasedinto cell

Drug passedthrough cell

Pinocytosis - a process allowing passage of large polar drugsinto a cell without actually crossing the cell membrane


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2. DRUG ABSORPTION

VebersparametersMolecular flexibity is important to drug absorptionToo many rotatable bonds is bad for absorptionThe polar surface of the molecule plays a roleMolecular weight is not a factor

Total no. of HBDs and HBAs 12Number of rotatable bonds 10

orPolar surface area < 140 AngstromsNumber of rotatable bonds 10

3. DRUG DISTRIBUTION

NotesOnce across the gut wall, drug enters blood vesselsCells lining blood vessels are loose fittingNo need to cross cell membranes

Drug can quickly cross blood vessel walls through pores betweencellsDrugs absorbed orally are first taken to the liverModification of the drug is possible by enzymes in the liver -drug metabolismA certain percentage of the absorbed drug is often deactivated bydrug metabolism in the liver before distribution occurs round thebody - first pass effectDrug is distributed evenly throughout blood supply within 1 minof absorption


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3. DRUG DISTRIBUTIONNotes

Uneven distribution round body due to uneven bloodsupplyRapid distribution from blood vessels to tissues and organs(leaky blood vessels)Drug has to enter a cell if target is within the cellBlood concentration drops rapidly after absorption due todistribution, macromolecular binding and storage in fattissue (e.g. barbiturates) or boneBlood brain barrier hinders polar drugs from entering brain

-tight fitting cells line the capillaries in the brain-capillaries have a coating of fat cells

Can increase polarity of peripherally acting drugs to reduceCNS side effectsPlacental barrier

Notes:Foreign chemicals are modified by enzyme catalysedreactions, mostly in liver - detoxification

Metabolic reactions also occur in blood, gut wall and otherorgans

Drug metabolites are products formed from drugmetabolism

Drug metabolites are usually less active or inactive(exception - prodrugs)

Modification of a structure may interfere or preventbinding interactions with a target (pharmacodynamics)

4. DRUG METABOLISM


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Notes:

4. DRUG METABOLISM

Orally absorbed compounds pass through the liver beforedistribution to the rest of the body

A percentage of orally absorbed drug is metabolised in theliver prior to distribution round the body - the first pass effect

Compounds absorbed by other routes avoid the first passeffect and circulate round the body before reaching the liver

A percentage of non-orally absorbed compounds neverreaches the liver due to distribution into fat, cells and tissue)

Notes:Metabolic reactions are defined as phase I or phase II

Most phase I reactions add a polar handleto the molecule

Phase II reactions are often carried out on functionalgroups which have been added by Phase I reactions

Increasing the polarity of a compound increases the rate ofdrug excretion (see drug excretion)

Cytochrome P450 enzymes catalyse phase I oxidations

4. DRUG METABOLISMPhase I and Phase II Reactions


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Certain foods affect the activity of cytochrome P450 enzymes

- brussel sprouts & cigarette smoke enhance activity- grapefruit juice inhibits activity

4. DRUG METABOLISMDrug-food interactions

Terfenadine (Seldane) - prodrug for Fexofenadine (Allegra)Metabolised by cytochrome P450 enzymesMetabolism slowed by grapefruit juiceBuild up of terfenadine leads to cardiac toxicityFexofenadine favoured in therapy over terfenadine

antihistamines

N

OH

OH

RTerfenadine R=CH3Fexofenadine R=CO2H

5. DRUG EXCRETION

Routes of excretion

Lungs - general anaesthetics

Skin (sweat)

Breast milk - nicotine

Bile duct - morphine

Kidneys - major excretion route


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5. DRUG EXCRETION

The kidneys

Vein

Renal a rtery

Arterioles

Glomerulus

Bladder

Nephron

Blood filtered at glomerulus - drugs and metabolites enter nephronWater absorbed back into blood vessels surrounding nephronConcentration gradient set up for drugs and metabolitesHydrophobic structures re-absorbed down concentration gradientPolar structures cannot cross cell membranes and are excretedMetabolic reactions increase polarity of drugs to increase their excretion

6. DRUG ADMINISTRATION

METHODS

OralSublingualRectal

Epithelial (topical drugs, eye drops)Inhalation (anti-asthmatics, general anaestheticsInjection (subcutaneous, intramuscular, intravenous, intrathecal)Implants


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6.1 Oral Administration

Common route for drug administration

Drug has to survive the gastrointestinal tract (GIT)

GIT consists of stomach, small and large intestine

GIT function - to break down food and absorb nutrients (stomach acidsand digestive enzymes)

Drug has to survive gastric acid (HCl)

Tablet / capsule design can protect some drugs from stomach acids

Drug has to be stable to digestive enzymes

NotesOrally taken drugs must pass through the cells lining the gut wall to reachthe blood supply - required to cross two fatty cell membranes

Very polar drugs are unlikely to cross fatty cell membranes and are

localised in the GIT - useful in designing drugs to target gut infections

Very hydrophobic drugs are poorly absorbed - dissolve in fat globulesfrom food resulting in poor surface contact with gut wall

6.1 Oral Administration


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NotesRespiratory system includes nose, airways, and lungs (trachea, bronchi,bronchioli, alveoli)

Function of lungs - to exchange gases with blood supply (O2in, CO2out)

Alveoli - air sacs with single cell walls surrounded by blood capillariesallowing fast efficient exchange of gases

Surface area is 500 square feet dealing with 20 kg air per day

Inhalation used for volatile gases (general anaesthetics) and anti-asthmatic

aerosols (salbutamol or Ventolin)

6.2 Inhalation - Respiratory System

NotesSome inhaled drugs cross the cells lining the alveoli to access the bloodsupply - required to cross two fatty cell membranes

Very polar drugs are unlikely to cross cell membranes - useful in targeting

anti-asthmatic drugs

Drugs entering the blood supply through the lungs avoid the first passeffect

6.2 Inhalation - Respiratory System


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NotesUsed for drugs which are poorly absorbed orally (e.g. morphine)

Injected drugs may damage area of injection directly (localisedinflammation and irritation)

Injected drugs have no cell membranes to cross in order to reach the bloodsupply - rapid distribution and fast effect.

No first pass effect through liver

High risk of toxicity or drug overdoses

More difficult to counter toxic effects

6.3 Injection

Types of injection methods

Intravenous - injection into veinsIntramuscular - injection into muscleSubcutaneous - injection under the skin surface

Intrathecal - injection into the spinal cordIntraperitoneal - injection into the abdominal cavityIntraocular - injection into the eye

Intravenous method is fastest but riskiestCan lower the risk by using intravenous drips

6.3 Injection


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NotesUsed for topical application of drugs (e.g. nicotine patches)Drugs cross the skin to reach the blood supplyNo first pass effectSolvents may aid absorption of drugsSkin in different parts of body has variable porosityChemicals are most easily absorbed where skin is thin (forearms)Chemicals that are soluble both in fat and water are most likely to beabsorbedAbsorption is increased if skin is moist or wet

6.4 Topical administration (transdermal absorption)

Maximum blood level concentration and time taken to reach it depends onmethod of absorptionConcentration decreases with time (drug metabolism and excretion)

6.5 Blood level concentrations of drugs

Blood

level

conc.

Time

Injection

Inhalation

Ingestion

Dermal


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Drug is linked to a synthetic polymer or to a protein-based polymerUseful for obtaining slow and constant release of the drug and avoiding spikesof blood concentration levels

7. Drug DeliveryPolymer-drug conjugates

O

O

OHn

HO

Polyethylene glycol (PEG)

HN

O

CO2Na n

Polyglutamate(PGA)

C

C

CH3

O

NH

CHOH

CH2

CH3 n

N-(2-Hydroxypropyl)methacrylamide (HPMA)

Examples of polymers

DRUG DESIGN AND DEVELOPMENT

Stages

1) Identify target disease2) Identify drug target

3) Establish testing procedures

4) Find a lead compound5) Structure Activity Relationships (SAR)6) Identify a pharmacophore7) Drug design- optimizing target interactions8) Drug design - optimizing pharmacokinetic properties9) Toxicological and safety tests10) Chemical development and production11) Patenting and regulatory affairs12) Clinical trials


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Rationale:Vary length and bulk of alkyl group to introduce selectivity

7.1 Vary Alkyl Substituents

Fit

Fit

NCH3

N CH3Fit

No Fit

StericBlock

N CH3

CH3

N

Binding region for N

Receptor 1 Receptor 2

Rationale:Vary length and bulk of alkyl group to introduce selectivity


Example:Selectivity of adrenergic agents for b-adrenoceptors over a-adrenoceptors


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Propranolol(b-Blocker)

OH

O NH

CH3

CH3H

Salbutamol(Ventolin)(Anti-asthmatic)

HOCH2

HO

HN

CCH3

OH

CH3

H

CH3

Adrenaline HO

HO

HN

CH3

OH

H

a-Adrenoceptor

H-Bondingregion

H-Bondingregion

H-Bondingregion

Van der Waalsbonding region

Ionicbondingregion


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ADRENALINE

a-Adrenoceptor

a-Adrenoceptor


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b-Adrenoceptor

ADRENALINE

SALBUTAMOL

b-Adrenoceptor


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b-Adrenoceptor

a-Adrenoceptor

SALBUTAMOL


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SALBUTAMOL

a-Adrenoceptor

SALBUTAMOL

a-Adrenoceptor


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SALBUTAMOL

a-Adrenoceptor

SALBUTAMOL

a-Adrenoceptor


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SALBUTAMOL

a-Adrenoceptor

SALBUTAMOL

a-Adrenoceptor


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a-Adrenoceptor


Synthetic feasibility of analogues

Feasible to replace alkyl substituents on heteroatoms with other alkylsubstituents

Difficult to modify alkyl substituents on the carbon skeleton of a leadcompound.


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..

N

O

O

NH2

7.2 Vary Aryl Substituents

NotesBinding strength of NH2as HBD affected by relative position of NO2Stronger when NO2is atparaposition

Metasubstitution:Inductive electron withdrawing effect

Para

substitution:Electron withdrawing effect due to resonance +inductive effects leading to a weaker base

..

N

O

NH2

ON

O

NH2

O

Vary substituents

Vary substitution pattern

RECEPTOR

Rationale: To explore target binding site for further binding

regions to achieve additional binding interactions

7.3 Extension - Extra Functional Groups

Unusedbindingregion

DRUG

RECEPTOR

DRUGExtrafunctionalgroup

Binding regions

Binding group

DrugExtension


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Example: ACE Inhibitors


EXTENSION

Hydrophobic pocket

Bindingsite

NH

N

O CO2

O

O

CH3

Bindingsite

NH

N

O CO2

O

O

CH3

(I)

Hydrophobic pocket

Vacant

Example: Nerve gases and medicines


NotesExtension - addition of quaternary nitrogenExtra ionic bonding interactionIncreased selectivity for cholinergic receptor

Mimics quaternary nitrogen of acetylcholine

Sarin(nerve gas)

O

P

FO(CHMe2)

CH3

Ecothiopate(medicine)

O

P

S

N

CH3

H3C

H3C

OEt

OEt

Acetylcholine

O

N

CH3

H3C

H3C

CH3

O

Ecothiopate(medicine)

O

P

S

N

CH3

H3C

H3C

OEt

OEt


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Example: Second-generation anti-impotence drugs


NotesExtension - addition of pyridine ringExtra van der Waals interactions and HBAIncreased target selectivity

ViagraN

N

CH3

S OO

CH3

N

HN

O

N

N

CH3

CH3

N

N

CH3

S OO

CH3

N

HN

O

N

HN

CH3

N

N

N

CH3

S OO

CH3

N

HN

O

N

HN

CH3

N

Example: Antagonists from agonists


HO

HO

HN

CH3

OH

H

Adrenaline

OH

O NH

CH3

CH3H

Propranolol(b-Blocker)

N

HN

NH2

Histamine

N

HN S

H3CHN

HNC

N

CH3

Cimetidine (T

Documents

Introduction to Medicinal Chemistry 1431.pdf