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How do Drugs Work?
Drugs
generally work by interacting with receptors on the surface of
cells or enzymes (which regulate the rate of chemical reactions)
within cells. Receptor and enzyme molecules
have a specific three-dimensional structure which allows only
substances that fit precisely to attach to it. This is often referred
to as a lock and key model.
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drugs work because by binding to the target receptor site,
they can either block the physiological function of the protein,
or mimics it's effect. If a drug causes the protein receptor
to respond in the same way as the naturally occurring substance,
then the drug is referred to as an agonist. Examples
of agonists are morphine, nicotine, phenylephrine,
and isoproterenol. Antagonists are drugs that interact
selectively with receptors but do not lead to an observed
effect. Instead they reduce the action of an agonist at the
receptor site involved. Receptor antagonists can be classified
as reversible or irreversible. Reversible antagonists readily
dissociate from their receptor. Irreversible antagonists form
a stable chemical bond with their receptor (eg, in alkylation).
Examples of antagonist drugs are: beta-blockers, such
as propranolol. |
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Instead
of receptors, some drugs target enzymes, which regulate the rate
of chemical reactions. Drugs
that target enzymes are classified as inhibitors or activators
(inducers). Examples of drugs that target enzymes are: aspirin,
cox-2 inhibitors and hiv protease inhibitors (see below).
Many
drug companies will design structural variants for compounds that
bind receptor sites in hope of making a compound that is more
effective. Until
recently design of new drugs was very difficult. Scientists had
no way to know what the binding site of the protein looked like.
Scientist now have a powerful new tool. Molecular modeling allows
researchers to view the 3-D structure of proteins and their binding
sites using data from X-ray crystallography and NMR spectroscopy
. The synthesis of several recent drugs (including HIV Protease
Inhibitors for treatment of AIDS) have been assisted using the
3-D structure of protein.
CASE
I: HOW ASPIRIN AND OTHER NONSTEROIDAL ANTI-INFLAMMATORY INHIBITORS
WORKS
Nonsteroidal
anti-inflammatory drugs work by interfering with the cyclooxygenase
pathway. The normal process begins with arachidonic acid, a dietary
unsaturated fatty acid obtained from animal fats. This acid is
converted by the enzyme cyclooxygenase to synthesize different
prostaglandins. The prostaglandins go on to stimulate many other
regulatory functions and reactionary responses in the body including:
inflammation and increased sensitivity to pain . Aspirin and other
NSAID's work by inhibiting this pathway.
Recent
research has shown that there are two types of cyclooxygenase,
denoted COX-1 and COX-2. Each type of cyclooxygenase lends itself
to producing different types of prostaglandins. COX-1 is located
in the stomach wall.
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pdb
fle: 1CVU (shown using the Jmol Applet)
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BY SELECTIVELY
BINDING TO THE ARACHIDONIC ACID SITE, NSAID INHIBIT THE
COX-2 ENZYME
SHOWN
TO LEFT: CYCLOOXYGENASE-2 (PROSTAGLANDIN SYNTHASE-2) COMPLEXED
WITH A NON-SELECTIVE INHIBITOR, INDOMETHACIN (ONLY THE A
CHAIN IS SHOWN WITH HEME AND INHIBITOR MOLECULE)
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How do NSAID
get to the active site?
ACCESS TO
THE COX-2 CATALYTIC SITE IS THROUGH THE MEMBRANE LIPID. CELECOXIB
INTERCALATES INTO THE MEMBRANE CORE AND THEN DIFFUSES ALONG A
PATH TO GAIN ACCESS TO THE HYDROPHOBIC BINDING SITE. OTHER DRUGS
MAY USE A SLIGHTLY DIFFERENT MECHANISM PROVIDING EVIDENCE FOR
THE FLEXIBLE
NATURE OF CYCLOOXYGENASE
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What
causes side effects in the case of aspirin? Why
does aspirin cause cause stomach upset but the newer NSAID drugs do
not?
The
two forms of cyclooxygenase have equal molecular weights and are very
similar in structure. However, the binding active site of COX-1 (located
in the stomach walls) is smaller than the similar site of COX-2, so
it accepts a smaller range of structures as substrates. In the stomach
COX-1 makes prostaglandin that seems to keep your stomach lining nice
and thick by stimulating mucous production; inhibiting this enzyme can
cause irritation of the stomach lining.
CASE
II: HOW DO AIDS ANTI-VIRAL DRUGS WORK?
Protease
inhibitors inhibit the activity of protease, an enzyme used by HIV
to cleave nascent proteins for final assembly of new HIV virons, and
so prevent viral replication. This was the second class of antiretroviral
drugs developed. Indinavir -- Trade name: CrixivanŽ was FDA approved
March 13, 1996. It was the eighth approved antiretroviral drug. Indinavir
was much more powerful than any prior antiretroviral drug; using it
with dual NRTIs set the standard for treatment of HIV/AIDS and raised
the bar the design and introduction of subsequent antiretroviral drugs.
Protease inhibitors changed the very nature of the AIDS epidemic from
one of a terminal illness to a somewhat manageable one.
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PDB
FILE: 1HPV (shown
using the Jmol Applet)
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CRIXIVAN
IS SHOWN BOUND TO THE PROTEASE ENZYME ACTIVE SITE. THE PROTEIN
BACKBONE IS SHOWN COLORED BY AMINO ACID.
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CASE
IIII: HUMAN GROWTH HORMONE RECEPTOR
Human
growth hormone (pink) binds two receptor molecules (gold) and thereby
induces signal transduction through receptor dimerization. Growth
hormone is naturally produced by the pituitary gland and is necessary
to stimulate growth in children. .
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pdb
file: 1hwh (shown using the Jmol Applet)
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1HWH HUMAN
GROWTH HORMONE WITH ITS 2 SOLUBLE BINDING PROTEIN -- RIBBON STRUCTURE
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CASE
IV: G -PROTEIN RECEPTOR
G
proteins are molecular switches that use GDP to control their signaling
cycle. The G protein system plays a central role in many signaling tasks,
making it a sensitive target for drugs and toxins. Many of the drugs
that are currently on the market, such as Claritin and Prozac, as well
as a number of drugs of abuse, such as heroin, cocaine and marijuana,
act at G-protein-coupled receptors in these signaling chains.
GPCRs
are also involved in aging,
cancer, cell growth stimulation, controlling metabolism ....
For
more information see G
Proteins.
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pdb
fle: 1GG2 (shown using the Jmol Applet)
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G protein
with bound GDP molecule.
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