Advanced Bioinformatics

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Advanced Bioinformatics Lecture 6 Pharmacology
and drug development
ZHU FENG zhufeng_at_cqu.edu.cn http//idrb.cqu.edu.cn
/ Innovative Drug Research Centre in CQU
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Table of Content

1. Modern drug development
2. Drug corresponding target
3. Mechanism of drug binding
4. Mechanism of drug action
5. Adrenoceptor cardiac function

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2013 ranking of the global top 10 pharmaceutical
companies based on revenue
40.0 15.0 3.8 1.8 60.6
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Revenue in billion U.S. dollars
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Top 10 drugs ranked by sales for Q1 2013
Rank Brand Name(s) Generic Name Sales (billion USD) Company Therapeutic Class Approval Year
1 Abilify Aripiprazole 1.5 Otsuka, BMS Depression 2002
2 Nexium Esomeprazole 1.4 AstraZeneca Dyspepsia 2000
3 Cymbalta Duloxetine 1.3 Eli Lilly Depression 2004
4 Crestor Rosuvastatin 1.3 AstraZeneca, Shionogi Cholesterol 2002
5 Seretide Fluticasone Salmeterol 1.3 GSK Asthma 2000
6 Humira Adalimumab 1.2 Abbott Rheumatoid arthritis 2002
7 Enbrel Etanercept 1.1 Amgen Rheumatoid arthritis 1998
8 Remicade Infliximab 1.0 JJ, Merck Rheumatoid arthritis 1998
9 Copaxone Glatiramer 0.9 Teva, Sanofi-Aventis Multiple sclerosis 1996
10 Neulasta Filgrastim 0.9 Amgen Neutropenia 2002
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Traditional drug design

• Random screening against disease assays
• Natural products, synthetic chemicals, etc
• Long design cycle 7-12 years
• High cost 350 million USD per marketed drug
• Too slow and costly to meet demand

Drug Discovery Today 2, 72-78 (1997)
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Modern drug development

• Rational drug design and testing
• Speed-up screening process
• Efficient screening (focused, target directed)
• Computer aided drug design (target directed)
• Integration of testing into design process
• Fail drugs fast (remove hopeless ones AEAP)

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Strategies for improving design cycle

• Smart screening
• High-throughput robotic screening
• Diversity of chemical compounds
• Combinatorial chemistry
• High expectation

Nature 384 Suppl., 2-7 (1996)
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Any other alternative approach?

• Current situation
• Molecular mechanism of disease processes,
  structural biology.
• Rising cost of experimental equipment and
  resources.
• Computer revolution (low cost, high power).
• Software development.
• Natural conclusion computer approach?

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Strategies for improving design cycle

• Computer-aided drug design
• Receptor 3D structure unknown
• Receptor-based drug design (QSAR)
• Receptor 3D structure known
• Ligand-based drug design (Docking)

Science 257, 1078-1082 (1992)
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The stages of development of a typical new drug
Overall cost per marketed compound is 250-500
million and the typical time scale is 8-12 years.
Only about 1 in 12 entering development succeeds
in reaching the market
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Key go/no-go decisions for developing a drug
Key decision gates in drug development
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Drug candidate selection Key questions and
pivotal studies
Bio-stability
Metabolism
Bioavailability
Cytotoxicity
Dosage
Synthesis
Formulation
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Drug safety indicators Key questions and pivotal
studies
Formulation
Dosage
Safety margin
Metabolism
Metabolism
Effects on heart
Effects on lung
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Pharmacology today with its various subdivisions
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Drug corresponding target
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Drug target receptor

• Receptors are the sites at which molecules such
  as hormones and neurotransmitters are recognised.
  
• A drug that binds to a receptor can be
• Agonist trigger the same events as the native
  ligand.
• Antagonist stop bind of the native agent without
  eliciting a response
• There are four superfamilies of receptors

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Types of receptor-effector linkage
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Drug target enzyme
Proteins catalyzing reactions required for
cellular function. Specific for particular
substrate or family of substrates. Inhibitor
restricts action of enzyme on its substrate.
Inhibitors may be irreversible or
reversible. Reversible inhibitors Competitive
Non-competitive. Enzyme inhibitors might be seen
to allow very fine control of cellular
processes.
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Drug target nucleic acids

• Designing compounds that can distinguish target
  nucleic acid sequences is not yet achievable.
• There are compounds with planar aromatic regions
  that bind in-between 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 for aiming at promoting cell death.

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Bio-chemical class distribution for successful
clinical trial targets
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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.

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Drug binding site in a cavity of protein HIV-1
protease
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Mechanism of drug binding and actions
Lock and key blocking gt stopping of protein
function HIV-1 protease complex with SB203238
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Covalent bonds

• The sharing of a pair of electrons between two
  atoms.
• A very stable interaction
• Requires hundreds of kilojoules (kJ) 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

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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

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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.

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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 is the ability of the bound drug to
  elicit a response
• 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
• There are 2 classes of antagonist
• Competitive which compete for the agonist
  binding site, and require higher agonist
  concentration to elicit a given response.
• Non-competitive 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 and control of cardiac
function
Adrenoceptor is receptor for two important
hormones adrenaline (????) and noradrenaline
(??????). Widely distributed, being responsible
for control of the stimulation and relaxation of
muscle, including the heart. Mediate the control
of cardiac function by the sympathetic nervous
system the parasympathetic nervous system
control is mediated by muscarinic acetylcholine
receptors. Remember that cytoplasmic Ca2
regulates the development of tension in muscles,
such as the heart.
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Case study Adrenoceptor 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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Function of adrenoceptors in heart 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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?1 and ?2-adrenoceptors activation leads to
constriction of vascular smooth muscle ?1 and
?2-adrenoceptors activation leads to Ca2
influx, relaxation of vascular smooth muscle, so
enhances contraction and increase heart rate. ?3
and ?4-adrenoceptors presence in heart is not
fully established, and their role is even more
uncertain.
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?1-adrenoceptor agonists
Treat hypotension through vasoconstriction,
leading to increased blood pressure. Also
valuable adjuncts to local anaesthetics, as
vasoconstriction can slow the systemic dispersal
of the anaesthetic. Drugs in this class include
Phenylephrine
Methoxamine
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?2-adrenoceptor agonists
Treat hypertension, 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
Clonidine
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?-adrenoceptor agonists
Treat hypotension, cardiac arrhythmias cardiac
failure. Stimulate the rate and force of cardiac
contraction, and lead to a drop in peripheral
vascular resistance. Drugs in this class include
Xamoterol
Dobutamine
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?1-Adrenoceptor antgonists
Inhibiting the action of endogenous
vasoconstrictors, resulting in vasodilation of
both arteries and veins, and thus reduction of
blood pressure. Treating hypertension and cardiac
failure. Drugs in this class include
Prazosin
Indoramin
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?2-Adrenoceptor antgonists
Just as ?2-adrenoceptor agonists unexpectedly
reduce vasoconstriction and lower cardiac
activity, their antagonists cause a rise in blood
pressure. Yohimbine is an ?2- adrenoceptor
antagonist.
Yohimbine
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?-Adrenoceptor antgonists
Treating hypertension, angina and ischemic heart
disease, also cause an increase in peripheral
resistance to blood flow, although this effect is
reversed on prolonged administration. Drugs in
this class include
Propanolol
Metoprolol
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Projects QA!
Biological pathway simulation
2. Computer-aided anti-cancer drug design
3. Disease-causing mutation on drug target
Any questions? Thank you!
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