Download Drug targets at molecular level

Drug targets at molecular
level
• Cell Structures:- Since life is made up of cells, then quite clearly drugs must act
on cells. The structure of a typical cell is shown in Fig.
• cell membrane:-All cells in the
human body contain a boundary
wall called the cell membrane. This
encloses the contents of the cell—
the cytoplasm.
• The cell membrane seen under the
electron microscope consists of two
identifiable layers. Each layer is
made up of an ordered row of
phosphoglyceride molecules such
as phosphatidylcholine (lecithin).
Each phosphoglyceride molecule
consists of a small polar headgroup, and two long hydrophobic
chains.
• In the cell membrane, the two layers of phospholipids are arranged such
that the hydrophobic tails point to each other and form a fatty,
hydrophobic centre, while the ionic head-groups are placed at the inner
and outer surfaces of the cell membrane (Fig. 2.3).
• This is a stable structure since the ionic, hydrophilic head-groups can
interact with the aqueous media inside and outside the cell, while the
hydrophobic tails maximize vander Waal’s bonding with each other and are
kept away from the aqueous environments. The overall result of this
structure is to construct a fatty barrier between the cell's interior and its
surroundings.
• The membrane is not just made up of phospholipids, however. There are a large variety of
proteins situated in the cell membrane (Fig. 2.4). Some proteins lie on the surface of the
membrane. Others are embedded in it with part of their structure exposed to one surface
of the membrane or the other. Other proteins traverse the whole membrane and have
areas exposed both to the outside and the inside of the cell.
• The extent to which these proteins are embedded within the cell membrane structure
depends on the type of amino acid present. Portions of protein which are embedded in
the cell membrane will have a large number of hydrophobic amino acids, whereas those
portions which stick out on the
surface will have a large
number of hydrophilic amino
acids. Many surface proteins
also have short chains of
carbohydrates attached
to them and are thus
classed as glycoproteins.
These carbohydrate
segments are thought to
be important towards cell
recognition.
• Within the cytoplasm there are several structures, one of which is the
nucleus. This acts as the 'control centre' for the cell. The nucleus contains the
genetic code—the DNA—and contains the blueprints for the construction of
all the cell's enzymes.
• There are many other structures within a cell, such as the mitochondria, the
golgi apparatus, and the endoplasmic reticulum etc.
Four main molecular targets:
• Different drugs act at different locations in the cell and there is no
one target site which we could pinpoint as the spot where drugs act.
• We need to magnify the picture, move down to the molecular level,
and find out what types of molecules in the cell are affected by
drugs. When we do that, we find that there are four main molecular
targets:
(1) lipids
(2) Carbohydrates
(3) proteins
(4) nucleic acids
Drug targets
Proteins
Receptors
Enzymes
Carrier proteins
Structural proteins (tubulin)
Lipids
Cell membrane lipids
Nucleic acids
DNA
RNA
Carbohydrates
Cell surface carbohydrates
Antigens and recognition molecules
Drug targets
•
Drug targets are large molecules - macromolecules
•
Drugs are generally much smaller than their targets
•
Drugs interact with their targets by binding to binding sites
•
Binding sites are typically hydrophobic pockets on the surface of
macromolecules
•
Binding interactions typically involve intermolecular bonds
•
Most drugs are in equilibrium between being bound and unbound to
their target
•
Functional groups on the drug are involved in binding interactions and
are called binding groups
•
Specific regions within the binding site that are involved in binding
interactions are called binding regions
Lipids as drug targets
• The number of drugs which interact with lipids are relatively small
and, in general, they all act in the same way—by disrupting the lipid
structure of cell membranes.
Eg.1
• Anesthetics work by interacting with the lipids of cell membranes to
alter the structure and conducting properties of the cell membrane.
‘Tunnelling molecules’
Eg. 1 The antifungal agent—amphotericin B (Fig. 2.5) interacts with the
lipids of fungal cell membranes to build 'tunnels' through the
membrane. Once in place, the contents of the cell are drained away and
the cell is killed.
• Amphotericin is a fascinating
molecule in that one half of the
structure is made up of double
bonds and is hydrophobic, while
the other half contains a series of
hydroxyl groups and is hydrophilic.
• It is a molecule of extremes and as
such is ideally suited to act on the
cell membrane in the way that it
does. Several amphotericin
molecules cluster together such
that the alkene chains are to the
exterior and interact favourably
with the hydrophobic centre of
the cell membrane.
• The tunnel resulting from this
cluster is lined with the hydroxyl
groups and so is hydrophilic,
allowing the polar contents of the
cell to escape (Fig. 2.6).
• Eg. 2
• Gramicidin A (Fig. 10.67)is a peptide containing 15 amino acids which is
thought to coil into a helix such that the outside of the helix is hydrophobic
and interacts with the membrane lipids, while the inside of the helix contains
hydrophilic groups, thus allowing the passage of ions.
• Therefore, gramicidin A could be viewed as an escape tunnel through the cell
membrane.
• In fact, one molecule of gramicidin would not be long enough to traverse the
membrane and it has been proposed that two gramicidin helices align
themselves end-to-end in order to achieve the length required (Fig. 10.68).
• Petide Valinomycin is another drug
which targets lipids.
• The peptides valinomycin (Fig. 10.64)
and gramicidin A (Fig. 10.67) both
act as ion conducting antibiotics and
allow the uncontrolled movement of
ions across the cell membrane.
• Unfortunately, both these agents
show no selective toxicity for
bacterial over mammalian cells and
are therefore useless as therapeutic
agents.
• Their mechanism of action is
interesting nevertheless.
Eg.3 Ion carriers -Valinomycin
• Valinomycin is a cyclic structure containing three molecules of L-valine,
three molecules of D-valine, three molecules of L-lactic acid, and three
molecules of D-hydroxyisovalerate.
• These four components are linked in an ordered fashion such that there is
an alternating sequence of ester and amide linking bonds around the cyclic
structure.
• This is achieved by the presence of a lactic or hydroxyvaleric acid unit
between each of the six valine units. Further ordering can be observed by
noting that the L and D portions of valine alternate around the cycle, as do
the lactate and hydroxyisovalerate units.
Mechanism of action:
• Since it is cyclic, it forms a doughnut-type
structure where the polar carbonyl
oxygens of the ester and amide groups
face inside, while the hydrophobic sidechains
of
the
valine
and
hydroxyisovalerate units point outwards.
• This is clearly favored since the
hydrophobic side-chains can interact via
van der Waals forces with the fatty lipid
interior of the cell membrane, while the
polar hydrophilic groups are clustered
together in the centre of the doughnut to
produce a hydrophilic environment.
• This hydrophilic centre is large enough to
accommodate an ion and it is found that a
'naked' potassium ion (i.e. no surrounding
water molecules) fits the space and is
complexed by the amide carboxyl groups
(Fig. 10.65).
• Valinomycin can therefore 'collect' a potassium ion from the inner surface of
the membrane, carry it across the membrane and deposit it outside the cell,
thus disrupting the ionic equilibrium of the cell (Fig. 10.66).
• Normally, cells have a high concentration of potassium and a low
concentration of sodium. The fatty cell membrane prevents passage of ions
between the cell and its environment, and ions can only pass through the cell
membrane aided by specialized and controlled ion transport systems.
• Valinomycin introduces an uncontrolled ion transport system which proves
fatal.
• Valinomycin is specific for potassium ions over sodium ions as sodium ions do
not lose their surrounding water 'coat' very easily and would have to be
transported as the hydrated ion. As such, they are too big for the central cavity
of valinomycin.
Carbohydrates as drug targets
• Until recently carbohydrates were not seen as useful targets for
drugs. The main role of carbohydrates in the cell were seen as being
of energy storage.
• It is now known as carbohydrates have important role to play in
various cellular processes such as cell recognition, regulation and
growth. Various disease states are associated with these cellular
processes. Eg. Bacteria and viruses have to recognize host cells
before they can infect them and so the carbohydrates molecules
involved in this cell recognition are crucial to the process.
• Designing drugs to bind to these carbohydrates may well block the
ability of bacteria and viruses to invade host cells.
• Cell recognition role is mainly played by carbohydrates linked to proteins
(called as glycoprotein) and to lipids( called as glycolipids). Such molecules
are referred as glycoconjugates.
• Usually protein or lipid portion of the molecule is embedded in cell
membrane with carbohydrate portion hanging free on the outside of the
membrane. This allows the carbohydrate portion to serve as tag which labels
and identifies the cell.
• One of the most important types of glycoconjugates is glycosphingolipids
which consists of a carbohydrate tag and ceramide anchor. The ceramide
portion is hydrophobic and is embedded in cell membrane and carbohydrate
portion lies out side and acts as molecular ‘tag’ for the cell.
Carbohydrate 'tag'
Ceramide 'anchor'
Carbohydrate 'tag'
HO
Cell
membrane
O
SUGARS O
O
HO
(CH2)16CH3
HN
O
OH
Carbohydrates
(CH2)12CH3
OH
Ceramide unit
• Drugs which are carbohydrates or contains carbohydrate as part of there
structure.
1. Antibiotic- eg. Streptomycin
2. Anti HIV drug- Eg. AZT
3. Antiherpes drug-Acyclovir
Acyclovir
Zidovudine
Streptomycin
Proteins and Nucleic acids as drug targets.
• The vast majority of drugs interact with proteins or nucleic acids.
• We will discuss them separately.