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CZ5225: Modeling and Simulation in Biology
Lecture 2: Drugs
Prof. Chen Yu Zong
Tel: 6874-6877
Email: [email protected]
http://xin.cz3.nus.edu.sg
Room 07-24, level 7, SOC1,
National University of Singapore
Definitions
Xenobiotic: A chemical that is not endogenous to an organism.
Endogenous: Made within.
Drug: A chemical taken that is intended to modulate the
current physiological status quo.
Ligand: A chemical that binds to another molecule, such as a
receptor protein.
Bioavailability: The amount or proportion of drug that
becomes available to the body following its administration.
Pharmacokinetics: What the body does to a drug.
Pharmacodynamics: What a drug does to the body .
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Drug action
A drug is a compound that can modify the response of a tissue
to its environment.
A drug will exert its activity through interactions at one or more
molecular targets.
• The macromolecular species that control the functions of
cells.
• May be surface-bound proteins like receptors and ion
channels or
• Species internal to cells, such as enzymes or nucleic acids.
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Drug-Receptor Lock and Key Model
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Drug Targets: Receptors
Receptors are the sites at which biomolecules such as
hormones, neurotransmitters and the molecules responsible
for taste and odour are recognised.
A drug that binds to a receptor can either:
• Trigger the same events as the native ligand - an agonist.
Or
• Stop the binding of the native agent without eliciting a
response - an antagonist.
There are four ‘superfamilies’ of receptors.
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Drug Targets:
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Drug Targets: Receptors
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Drug Targets: Receptors
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Drug Targets:
Receptors
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Drug Targets: Enzymes
They are proteins that catalyse the reactions required for
cellular function.
Generally specific for a particular substrate, or closely related
family of substrates.
Molecules that restrict the action of the enzyme on its substrate
are called inhibitors.
Inhibitors may be irreversible or reversible.
Reversible inhibitors may be:
• Competitive.
• Non-competitive.
Enzyme inhibitors might be seen to allow very ‘fine control’ of
cellular processes.
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Drug targets: Nucleic acids
Potentially the most exciting and valuable of the available drug
targets.
BUT designing compounds that can distinguish target nucleic
acid sequences is not yet achievable.
There are compounds with planar aromatic regions that bind inbetween the base pairs of DNA or to the DNA grooves.
These generally inhibit the processes of DNA manipulation
required for protein synthesis and cell division.
• Suitable as drugs for applications where cell death is the
goal of therapy - such as in the case of the treatment of
cancer.
• Name another use where cell death is desirable.
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Mechanisms and Specificity of Drug Binding
The majority of binding and recognition occurs through noncovalent interactions.
These govern:
• The folding of proteins and DNA.
• The association of membranes.
• Molecular recognition (e.g. interaction between an
enzyme and its substrate or the binding of an antibody).
They are generally weak and operate only over short
distances.
As a result large numbers of these interactions are necessary
for stability, requiring a high degree of complementarity
between binding groups and molecules.
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Drug Binding Site
HIV-1 protease
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Mechanism of Drug Binding and Actions
Drug and protein:
Lock and key mechanism, blocking=>stopping of protein function
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Protein
Surface
X-Ray Diffraction Structure Of Hiv-1 Protease Complexed With SB203238
(Drawn from: Brookhaven database file: 1hbv.pdb.
K.A.Newlander, J.F.Callahan, M.L.Moore, T.A.Tomaszek, W.F.Huffman A Novel Constrained
Reduced-Amide Inhibitor Of HIV-1 Protease Derived From The Sequential Incorporation Of
Gamma-Turn Mimetics Into A Model Substrate J.Med.Chem. 1993, 36, 2321.)
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Covalent bonds
The ‘sharing’ of a pair of electrons between two atoms.
These electrons largely occupy the space between the nuclei of
the two atoms.
• A very stable interaction
• Requires hundreds of kilojoules to disrupt.
Compounds that inhibit enzymes through formation of covalent
interactions are called ‘suicide inhibitors’.
Not all covalent bond formation is irreversible
• Hydrolysis.
• Action of repairing proteins.
Consult with your Biochemistry textbook
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Non-covalent interactions
The forces involved are:
• Hydrogen bonds
• van der Waals forces
• Ionic / electrostatic interactions
• Hydrophobic interactions.
Generally, such interactions are weak
•vary from 4-30 kJ/mol.
Details later
Selectivity, toxicity and therapeutic index
Drugs may bind to both their desired target and to other
molecules in an organism.
If interactions with other targets are negligible then a drug
is said to be specific.
In most cases drugs will show a non-exclusive preference
for their target - selective.
The interaction with both their intended target and other
molecules can lead to undesirable effects (side effects).
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Selectivity, toxicity and therapeutic index
Establish the concentrations at which the drug exerts its
beneficial effect and where the level of side effects becomes
unacceptable.
Commonly used values are ED50 and LD50.
For obvious reasons LD50 tests are not carried out on human
volunteers!
One measure of the margin of safety is the therapeutic index.
Therapeutic index = LD50 / ED50
Drugs with low therapeutic indices are only used in ‘life or
death’ type situations.
Exercise: it can be argued that the ratio LD1 / ED99 might be a more realistic
estimate of safety. Why?
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Agonists & antagonists
Activity of a drug is the result of two independent factors:
• Affinity is the ability of a drug to bind to its receptor.
• Efficacy describes the ability of the bound drug to elicit a
response.
The ‘two state model’. Receptors can be inactive or activated.
An agonist stabilises the active state preferentially.
An antagonist shows no preference or it stabilises the resting
state.
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Agonists & antagonists
Activity of a drug is the result of two independent factors:
• Affinity is the ability of a drug to bind to its receptor.
• Efficacy describes the ability of the bound drug to elicit a
response.
The ‘two state model’. Receptors can be inactive or activated.
An agonist stabilises the active state preferentially.
An antagonist shows no preference or it stabilises the resting
state.
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Agonists & antagonists
The efficacy of a compound in the two state model is the
degree of selectivity for stabilising the active or resting state
of the receptor.
The degree of selectivity can be expressed in terms of the
ratio of the equilibrium binding constant, K for each receptor
state.
• Kactive / Kresting > 1, then the compound is an agonist.
The higher the ratio, the higher will be the efficacy.
• Kactive / Kresting  1, then the compound is an antagonist.
The smaller the ratio, the higher will be the efficacy.
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Agonists & antagonists
There are 2 classes of agonist:
• Full agonists – which elicit the maximum possible
response at some concentration
• Partial agonists – which never elicit the maximum
possible response from the receptor.
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Agonists & antagonists
There are also 2 classes of antagonist:
• Competitive antagonists – which compete for the
agonist binding site, and require higher agonist
concentration to elicit a given response.
• Non-competitive agonists – these bind at a site other
than the agonist binding site, or even to a
completely different molecular target. The result is
the lowering of the maximum possible response in
addition to the usual antagonist effect of ‘displacing’
agonist activity to higher concentration.
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Case Study: Adrenoceptor agonists and
antagonists and control of cardiac function
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Case Study: Adrenoceptor agonists and
antagonists and control of cardiac function
Adrenoceptors
The receptors for adrenaline (epinephrine) and noradrenaline
(norepinephrine).
Also called adrenergic receptors.
Widely distributed, being responsible for control of the stimulation
and relaxation of muscle, including the heart.
Adrenoceptors mediate the control of cardiac function by the
sympathetic nervous system; the parasympathetic nervous
system control is mediated by muscarinic acetylcholine receptors.
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NH2
CO2H
HO
NH2
HO
CO2H
HO
Tyrosine
DOPA
OH
NH2
HO
NH2
HO
HO
HO
Norepinephrine
OH
HO
Dopamine
Route of the biosynthesis of
epinephrine and norepinephrine
H
N
CH3
HO
Epinephrine
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Case Study: Adrenoceptor agonists and
antagonists and control of cardiac function
Adrenoceptors are divided into 5, or possibly 6 types: 1,
2, 1, 2, 3, and potentially 4.
They are all G-protein coupled receptors.
The secondary messengers for the 1 adrenoceptors are
inositol triphosphate and diacylglycerol.
All other adrenoceptors have cAMP as their principal
secondary messenger.
Remember that cytoplasmic [Ca2+] regulates the
development of tension in muscles, such as the heart.
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Case Study:
Adrenoceptor
agonists and
antagonists and
control of
cardiac function
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Case Study: Adrenoceptor agonists and
antagonists and control of cardiac function
The activation of  and  adrenoceptors usually elicits opposing
responses:
•  receptor activation leads to constriction of veins and
arterioles.
•  receptor activation leads to dilation of veins and arterioles.
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Presence and function of adrenoceptors and the heart and
vascular system.
Epinephrine administered rapidly intravenously has a number of
simultaneous effects that contribute to a rapid rise in blood
pressure on its administration.
• A rise in the strength of ventricular contraction (a positive
inotropic action)
• The heart rate is increased (a positive chronotropic action)
• Blood vessels become constricted.
Noting the opposing roles of  and  receptors, it may be no
surprise to discover that administration regimes other than rapidly
intravenous injection can have quite different effects.
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Adrenoceptors: Signalling Process
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Adrenoceptors:
Signalling
Process
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1-Adrenoceptors: These are less abundant than adrenoceptors.
They couple to phospholipases C and D, to certain Ca2+
channels, and a number of ion channels allowing modification
of cellular cation content, including K+ and Na+.
Stimulation of 1-adrenoceptors does not lead to elevated
cAMP levels within the cell, and may even reduce cAMP
levels.
1-Adrenoceptor stimulation leads to formation of 1,4,5inositoltriphosphate and diacylglycerol.
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1-Adrenoceptors:
Inositoltriphosphate releases Ca2+ from intracellular
stores, and this may explain the observed increase in
force of contraction upon 1-adrenoceptor activation.
Their activation leads to constriction of vascular smooth
muscle.
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2-Adrenoceptors: Present in only very low levels in the heart.
Their activation leads to constriction of vascular smooth muscle.
1 and 2-Adrenoceptors: The ratio of 1 to 2-Adrenoceptors is
about 65:35 in the atria, and around 75:25 in the ventricles.
These receptors both lead to increases of [cAMP] following
stimulation.
This in turn activates protein kinase A, which can phosphorylate,
amongst other proteins, certain Ca2+ channels, leading to an influx
of Ca2+ ions, and so enhances contraction.
-Adrenoceptor agonists also increase heart rate.
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Only the 1 receptor is thought to be involved in the exerciseinduced increase in heart rate bought about by noradrenaline.
Adrenaline, on the other hand, may function primarily through the
2-adrenoceptors.
2-adrenoceptor activation also leads to relaxation of vascular
smooth muscle.
3, and potentially 4-Adrenoceptors: The presence of these in
the heart is not fully established, and their role, if present, is even
more uncertain.
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Adrenoceptor agonists
1-Adrenoceptor agonists: These can be used to treat
hypotension through vasoconstriction, leading to increased
blood pressure and cardiac arrhythmias through activation
of vagal reflexes.
Also valuable adjuncts to local anaesthetics, as
vasoconstriction can slow the systemic dispersal of the
anaesthetic.
Drugs in this class include phenylephrine and
methoxamine.
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Adrenoceptor agonists
2-Adrenoceptor agonists: Despite the tendency of adrenoceptor agonists to cause vasoconstriction, these
can be used to treat hypertension.
This unexpected activity occurs through action at the
CNS, reducing signal to the heart and so lowering
cardiac activity and constriction of the peripheral
vasculature.
Drugs in this class include methyldopa and clonidine.
Clonidine can also be used in protection against migrane.
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-Adrenoceptor agonists:
• These can be used to treat hypotension, cardiac
arrhythmias and cardiac failure.
• They stimulate the rate and force of cardiac
contraction.
• Simultaneously, they lead to a drop in peripheral
vascular resistance.
• These combined effects can result in palpitations,
sinus tachycardia and serious arrhythmias.
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-Adrenoceptor agonists:
Drugs in this class include xamoterol and dobutamine.
2-Adrenoceptor agonists lead to muscle relaxation
and so find use in treatment of asthma (salbutamol) and
delay in the onset of labour. (ritodrine).
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Adrenoceptor antagonists
1-Adrenoceptor antgonists: Antagonism (or ‘blockade’) of
1-adrenoceptors inhibits the action of endogenous
vasoconstrictors, resulting in vasodilation of both arteries and
veins, and thus reduction of blood pressure.
These drugs are, therefore, useful in the treatment of
hypertension and cardiac failure.
Prazosin and indoramin fall into this class of compounds.
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Adrenoceptor antagonists
2-Adrenoceptor antagonists: Just as 2adrenoceptor agonists unexpectedly reduce
vasoconstriction and lower cardiac activity, their
antagonists cause a rise in blood pressure through
reversal of these effects.
Yohimbine is an 2-adrenoceptor antagonist.
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-Adrenoceptor antagonists: These can be used to treat
hypertension, angina, cardiac arrhythmias and ischemic heart
disease.
The effects of -adrenoceptor antagonists (‘-blockers’) are only
evident when the heart is under stress or increased workload.
Under these circumstances, they preclude or attenuate increases
in the rate and force of cardiac contraction.
They also cause an increase in peripheral resistance to blood
flow, although this effect is reversed on prolonged administration.
Drugs in this class include propanolol and metoprelol.
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