Advanced Bioinformatics
Lecture 6: Pharmacology and drug development
ZHU FENG
zhufeng@cqu.edu.cn
http://idrb.cqu.edu.cn/
Innovative Drug Research Centre in CQU
创新药物研究与生物信息学实验室
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
2
2013 ranking of the global top 10 pharmaceutical
companies based on revenue
40.0
+
15.0
+
3.8
+
1.8
=
60.6
Revenue in billion U.S. dollars
3
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
Depression
2004
4
Crestor
Rosuvastatin
1.3
Eli Lilly
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
Rheumatoid arthritis
1998
9
Copaxone
Glatiramer
0.9
J&J, Merck
Teva, SanofiAventis
Multiple sclerosis
1996
10
Neulasta
Filgrastim
0.9
Amgen
Neutropenia
2002
4
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)
5
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)
6
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)
7
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?
8
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)
9
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
10
Key go/no-go
decisions for
developing a
drug
Key decision
gates in drug
development
Drug candidate selection
Key questions and pivotal studies
Bio-stability
Metabolism
Bioavailability
Cytotoxicity
Dosage
Synthesis
Formulation
12
Drug safety indicators
Key questions and pivotal studies
Formulation
Dosage
Safety margin
Metabolism
Metabolism
Effects on heart
Effects on lung
13
Pharmacology today with its various subdivisions
14
Drug & corresponding target
15
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
16
Types of receptor-effector linkage
17
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.
18
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.
19
Bio-chemical class distribution for successful & clinical trial targets
Fig 1 BioChemical Class Distribution for Successful Targets (348)
Channels and Transporters
12%
Receptor
24%
Factors and Regulators
6%
Nuclear Receptor
4%
Binding protein/Antigen
4%
Enzyme
46%
Structure Proteins
3%
Nucleic Acid
1%
Fig 2 BioChemical Class Distribution for Clinical Trial Targets (295)
Receptor
24%
Channels and Transporters Factors and
8%
Regulators Nuclear Receptor
11%
1%
Binding protein/Antigen
5%
Structure Proteins
3%
Enzyme
40%
Nucleic Acid
8%
20
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.
21
Drug binding site in a cavity of protein
HIV-1 protease
22
Mechanism of drug binding and actions
Lock and key: blocking => stopping of protein function
HIV-1 protease complex with SB203238
23
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
24
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
25
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).
26
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.
27
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.
28
Case study
Adrenoceptor and control of cardiac function
Adrenoceptor is receptor for two important hormones:
adrenaline (肾上腺素) and noradrenaline (去甲肾上腺素).
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.
29
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.
30
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.
31
1 and 2-adrenoceptor’s activation leads to
constriction of vascular smooth muscle
1 and 2-adrenoceptor’s activation leads to Ca2+
influx, relaxation of vascular smooth muscle, so
enhances contraction and increase heart rate.
3 and 4-adrenoceptor’s presence in heart is not fully
established, and their role is even more uncertain.
32
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
33
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
34
-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
35
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
36
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
37
-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
38
Projects Q&A!
1. Biological pathway simulation
2. Computer-aided anti-cancer drug design
3. Disease-causing mutation on drug target
Any questions? Thank you!
39