Transcript Essential Bioinformatics and Biocomputing (LSM2104

CZ3253: Computer Aided Drug design
Lecture 1: Drugs and Drug Development
Part I
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
History
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History
Ancient knowledge of the materials that could relieve
pain, alter moods and perceptions, aid against infection,
poison etc.
The first written treatises were generated by the Chinese
e.g. Pen Tsao was written ~2700 B.C., describing uses
and classifications of medicinal plants.
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History
The ancient Egyptians by 1550 B.C. had written
prescriptions using a range of pharmaceutically
active ingredients and vehicles for their delivery. At
about the same time, similar medical advances were
being made in Babylonia and India.
Between about 400-300 B.C. the Greeks made
enormous advances in the knowledge of anatomy
and physiology.
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History
Philippus Theophrastus Bombastus von Hohenheim
(1493-1541), also known as Aureolus Paracelcus, took
up the pharmacological baton.
He is often referred to as the ‘grandfather of
pharmacology’ and also the ‘grandfather of toxicology’
because of his impact on the understanding between
dose and response
“All things are poisons, for there is nothing without
poisonous qualities. It is only the dose which makes
a thing a poison”.
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History
No real further advances until the sciences of
chemistry and physiology had developed:
• To provide pure compounds.
• Allow careful monitoring of their physiological
effects.
This combination of circumstances arose in the early
19th Century.
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History
Modern Drug Development
Random screening against disease assays
Natural products, synthetic chemicals
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 as early as
possible)
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Drug Development
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Traditional Drug Design
Methods: Random screening
• Long design cycle: 7-12 years.
• High cost: $350 million USD per
marketed drug.
Drug Discovery Today 2, 72-78 (1997)
Too slow and costly to meet demand.
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Strategies for improving
design cycle:
• Smart screening:
– High-throughput robotic screening.
• Diversity of chemical compounds:
– Combinatorial chemistry.
Nature 384 Suppl., 2-7 (1996)
High expectation.
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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:
• QSAR.
– Receptor 3D structure known:
• Ligand-protein docking.
Science 257, 1078-1082 (1992)
Definition of receptor given later
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle
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Modern Drug Design Cycle:
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Modern Drug
Design Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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Modern
Drug
Design
Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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Modern Drug Design Cycle:
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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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Drug
targets
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Drug targets
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