CZ3253: Computer Aided Drug design Lecture 2: Drugs (Pharmacology) and Drug Development Part II...
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Transcript of CZ3253: Computer Aided Drug design Lecture 2: Drugs (Pharmacology) and Drug Development Part II...
CZ3253: Computer Aided Drug designCZ3253: Computer Aided Drug design
Lecture 2: Drugs (Pharmacology) and Drug Lecture 2: Drugs (Pharmacology) and Drug DevelopmentDevelopment
Part II Part II
Prof. Chen Yu ZongProf. Chen Yu Zong
Tel: 6874-6877Tel: 6874-6877Email: Email: [email protected]@nus.edu.sghttp://xin.cz3.nus.edu.sghttp://xin.cz3.nus.edu.sg
Room 07-24, level 7, SOC1, Room 07-24, level 7, SOC1, National University of SingaporeNational University of Singapore
22
Mechanisms and Specificity of Drug Binding
The majority of binding and recognition occurs through non-
covalent 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.
33
Drug Binding Site Drug Binding Site
HIV-1 protease
44
Mechanism of Drug Binding and ActionsMechanism of Drug Binding and Actions
Drug and protein:
Lock and key mechanism, blocking=>stopping of protein function
55
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.)
ProteinSurface
66
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
Essential Bioinformatics and BiocomputEssential Bioinformatics and Biocomputing (LSM2104)ing (LSM2104)
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
88
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).
99
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?
1010
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.
1111
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.
1212
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.
1313
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.
1414
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.
1515
Case Study: Adrenoceptor agonists andantagonists and control of cardiac function
1616
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.
1717
OH
NH2
CO2H OH
NH2OH
CO2H
NH2
OH
OHNH2
OH
OH
OH
NH
OH
OH
OH
CH3
Tyrosine DOPA
Norepinephrine Dopamine
Epinephrine
Route of the biosynthesis of epinephrine and norepinephrine
1818
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.
1919
Case Study:
Adrenoceptor
agonists and
antagonists and
control of
cardiac function
2020
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.
2121
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.
2222
Adrenoceptors: Signalling Process
2323
Adrenoceptors:
Signalling
Process
2424
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 1,4,5-
inositoltriphosphate and diacylglycerol.
2525
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.
2626
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.
2727
Only the 1 receptor is thought to be involved in the exercise-
induced 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.
2828
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.
2929
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.
3030
-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.
3131
-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).
3232
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.
3333
Adrenoceptor antagonists
2-Adrenoceptor antagonists: Just as 2-
adrenoceptor 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.
3434
-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.