Drugs are chemicals that interact with the body's chemical reactions.
1. Cell Structure as a Drug Target
Drugs act on cells because life is made of cells.
All cells in the human body have a boundary wall called the cell membrane, which encloses the cytoplasm.
Cell membrane contains two layers of “phosphoglyceride molecules”.
Each phosphoglyceride molecule contains:
A small polar head group
Two long hydrophobic chains
Cell Membrane
The cell membrane is composed of a bilayer of fatty molecules, making it difficult for polar molecules or ions to move in and out of the cell.
Examples of transport include the movement of sodium and potassium ions across the membrane, crucial for nerve function.
Endocytosis
Endocytosis is the process by which cells absorb molecules (such as proteins) by engulfing them.
Used by all cells because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane.
Exocytosis
The reverse of endocytosis is called exocytosis.
Also known as “reverse pinocytosis” and is the durable process by which a cell directs the contents out of the cell membrane.
These membrane-bound vesicles contain soluble proteins.
Pinocytosis
Pinocytosis (liquids):
A method by which molecules can enter cells without passing through cell membranes.
The molecule is ‘engulfed’ by the cell membrane and taken into the cell in a membrane-bound vesicle.
The process when the cell engulfs already-dissolved or broken-down food.
Used primarily for the absorption of extracellular fluids. The cell takes in surrounding fluids, including all solutes present.
Phagocytosis
Phagocytosis (solids):
Meaning "eating cell process" and is the cellular process of engulfing solid particles by the cell membrane.
A specific form of endocytosis involving the vesicular internalization of solid particles.
It is a major mechanism used to remove pathogens and cell debris.
Bacteria, dead tissue cells, and small mineral particles are all examples of objects that may be phagocytosed.
Engulfs whole particles, which are later broken down by enzymes and absorbed into the cells.
Molecular Weight and Cell Entry
When the size of the molecular weight is less than 200, the drug molecule can enter by squeezing through the gaps between the cells rather than by passing through cells.
Thus, highly polar molecules can reach tissues without having to cross cell membranes, as long as their molecular weight is less than 200.
2. Lipids as Drug Targets
The number of drugs which interact with lipid is relatively small and, in general, they all act in the same way – by disrupting the lipid structure of cell membrane.
The antifungal agent “amphotericin” interacts with the lipids of the cell membranes to form ‘tunnels’ through the membrane. The contents of the cell are drained away and the cell is killed.
Amphotericin has one half of the structure is made up of double bonds, hydrophobic while the other half contains a series of hydroxyl group, hydrophilic. This ideally suited to act on cell membrane.
The tunnel resulting from this cluster is lined with hydroxyl groups and so is allowing the polar contents of the cell to escape.
3. Carbohydrates as Drug Targets
Carbohydrates are polyhydroxy structures. There are very few clinically used drugs that act on carbohydrate targets.
However, this may change in the future. Carbohydrates play important roles in various cellular processes such as:
Cell recognition
Regulation
Growth
Various disease states are associated with these cellular processes.
There are many drugs that contain carbohydrates as part of their structure.
For example, ‘glycosidic antibiotics, glycoside digoxin, anti-HIV drug, antiherpes drug (acyclovir) etc.
The basic function of such drugs is to bring down the breakage of links between sugar part associated with the cell, ultimately inactivating the cell.
Carbohydrate structures offer tremendous potential for novel drugs in the future; e.g; glycoconjugates is a class of compound called glycosphingolipid.
Glycosphingolipids
Glycosphingolipids are made up of three components:
A carbohydrates which is highly variable and complex
Sphingosine
A fatty acid (stearic acid)
The portion of the molecule consisting of the sphingosine and the fatty acid is called a ceramide.
The ceramide portion of the molecule is hydrophobic and is embedded within the cell membrane, act as a anchor for the highly polar carbohydrate section.
The portion lies outside the cell membrane and acts as the molecular ‘tag’ which labels and identify for the cell.
4. Proteins as Drug Targets
The vast majority of drugs used in medicine are targeted on proteins and nucleic acids.
Molecules such as amino acids are polar structures and cannot pass through the hydrophobic cell membrane.
The carrier proteins are hydrophobic on the outside and can float freely through the cell membrane.
At the outer surface, bind the polar molecule (e,g. an amino acid), ‘wrap it up’ into the hydrophilic pocket ferry it across the membrane to release it on the other side.
Carrier proteins are not identical and are specific carrier proteins for the different molecules to cross the membrane.
The carrier proteins accept the drugs and carries it across the cell membrane, delivering the drug into the cell.
Important drug, cocaine and tricyclic antidepressants acts in this way.
5. Receptors
A protein in the cell membrane of a nerve or target organ with which a transmitter substance or drug can interact to produce a biological response.
When the chemical messenger fits into the binding site, it ‘switches on’ the receptor molecules and message is received.
The chemical message does not undergo a chemical reaction. It fits into the binding site of the receptor protein, passes on its message and leaves unchanged.
How the Message Gets Received
There are two main components involved:
Ion exchange
Membrane – bound enzyme
Cell Membrane Properties
The cell membrane is made up of a bilayer of fatty molecules, and in the middle of the cell membrane is “fatty and hydrophobic”.
These barrier makes it difficult for polar molecules or ion to move in and out of the cell, e.g; the movement of sodium and potassium ion across the membrane is crucial to function the nerve.
Ion channels are protein complexes which traverse the cell membrane and consist of several protein subunits.
The Centre of the complex is hollow and is lined with polar amino acids to give a hydrophilic core.
Ion Channels and Their Control
Ions can now cross the fatty barriers of the cell membrane by moving through these hydrophilic channels or tunnels or ‘lock-gate’ which open or closed as required, and controlled by the receptors proteins sensitive to an external chemical messenger.
In fact the receptor protein are the integral part of the ion complex channels.
When a chemical messenger binds to the external binding site of receptor protein, the receptor protein changes the shape, causes the receptor to change shape , opening up the lock- gate and allow to pass through the ion channel (induced –fit theory) to cytoplasm.
Synaptic transmission of signals between neurons usually involves ion channels.
Membrane-Bound Enzyme Activation
A receptor can pass on a message from a chemical messenger to the cell if the receptor also doubles up as an enzyme.
The receptor protein is embedded within the cell membrane, with part of its structure exposed to the outer surface of the cell and part of its structure exposed on the inner surface of the membrane.
The outer surface contains a binding site for the chemical messenger, and the inner surface has the active site, which is closed in the resting state.
When a chemical messenger binds to the receptor, it causes a change in shape, opens up the active site, and leads to a chemical reaction within the cell.
As long as the messenger is bound, the active site remains open, and so a neurotransmitter molecule can amplify its signal by binding long enough for several reactions to take place.
6. Enzymes (Modern Trend), (Isoenzymes)
Protein-based chemicals responsible for the completion (break down etc..) of biochemical reaction in the body.
The search continues for new enzyme inhibitors, especially which are selective for a specific isozyme
The non-steroidal anti-inflammatory drug Indomethacin used to treat the inflammatory diseases such as rheumatoid arthritis by inhibiting the enzyme cyclo-oxygenase.
This enzyme is involved in the biosynthesis of prostaglandins - agents responsible for the pain and inflammation of rheumatoid symptoms of the disease and vice versa.
There are two isozymes for the cyclo-oxygenase (COX-1 and COX-2), both carry the same reactions, but COX-1 is the isozyme which is active under normal healthy conditions.
The COX-2 which is dormant, become activated and produced excess inflammatory prostaglandins.
Therefore, drugs are being developed to be selective for COX-2 isozyme, so that only the production of inflammatory prostaglandins is reduced.
Enzyme Inhibitors Against Microorganisms
There are many fungal strains that produce metabolites (penicilline) which are toxic to bacteria but not themselves.
This gives the fungi an advantage over their microbial competitors when competing the nutrients.
The antifungal agent “fluconazole “ inhibits a fungal demethylase enzyme involved in steroidal biosynthesis. This enzyme is also present in humans, but the structural differences between the two enzymes are significantly different.
Enzyme Inhibitors Against Viruses
Enzyme inhibitors are extremely important in the battle against viral infections (herpes virus and HIV).
Successful antivirus drugs include acyclovir for HERPES and zidovudine for HIV.
Acyclovir has incomplete sugar ring which serves as the DNA chain terminator and phosphorylated to an active triphosphate form.
7. Nucleic Acids as Drug Targets
Drugs acting on DNA:
Intercalating cytostatic agents
Alkylating agents
Chain ‘cutter’
Intercalating Cytostatic Agents
Compounds that can slip between the layers of nucleic acid base pairs and disrupt the shape of the double helix and prevent the replication and transcription, e.g., antibacterial agent proflavine.
The highly effective anti-malarial agent quinine /chloroquine - can attack the malarial parasite by blocking DNA transcription as part of its action. This is due to the flat heteroaromatic structure which can intercalate DNA.
Aminoacridine agents (anti-bacterial agents) such as proflavine which were used in the Second World War to treat surface wounds. The flat tricyclic ring intercalate the between the DNA base pair while the amino cations bonds with the negatively charged phosphate groups on the sugar-phosphate backbone.
Alkylating Agents
Alkylating agents are highly electrophilic compounds which will react with nucleophiles to form strong covalent bonds.
There are several nucleophilic groups in DNA, e.g., 7-nitrogen of guanine.
Miscoding due to alkylated guanine units is also possible. This miscoding ultimately leads to an alteration in the amino acid sequence of proteins, which leads to disruption of protein structure and functions.
Alkylating drugs have been useful in the treatment of cancer. Tumour cells often divide more rapidly than normal cells and so disruption of DNA function will affect these cells more drastically than normal cells.
Drugs Acting by Chain Cutting
Bleomycin is a large glycoprotein able to cut the strand of DNA and prevent the enzyme DNA ligase from repairing the damage.
It seems to act by abstracting hydrogen atom from DNA, resulting radicals react with the oxygen to form peroxy species which then fragment.
The drug is useful against certain type of skin cancer.
Drugs Acting on RNA
The primary structure of RNA is the same as DNA, with two exceptions:
Ribose is the sugar component rather than deoxyribose, while uracil replaces thymine as one of the bases.
Base pairing between nucleic acid bases can occur in RNA, with adenine pairing to uracil and cytosine pairing to guanine.
The pairing is between bases within the same chain, and it does not occur for the whole length of the molecules.