Drug targets
From DrugPedia: A Wikipedia for Drug discovery
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| - | ''' | + | The term '''biological target''' is frequently used in pharmaceutical research to describe the native protein in the body whose activity is modified by a drug resulting in a desirable therapeutic effect. In this context, the biological target is often referred to as a '''drug target'''. |
| - | + | ||
| - | + | ==Drug targets Mechanism== | |
The external stimulus (i.e., chemical substance) physically binds to the biological target.The interaction between the substance and the target may be: | The external stimulus (i.e., chemical substance) physically binds to the biological target.The interaction between the substance and the target may be: | ||
| - | * noncovalent | + | * '''noncovalent''' |
| - | * reversible covalent - A chemical reaction occurs between the stimulus and target in which the stimulus becomes chemically bonded to the target, but the reverse reaction also readily occurs in which the bond can be broken. | + | * '''reversible covalent''' - A chemical reaction occurs between the stimulus and target in which the stimulus becomes chemically bonded to the target, but the reverse reaction also readily occurs in which the bond can be broken. |
| - | * irreversible covalent - The stimulus is permanently bound to the target through irreversible chemical bond formation. | + | * '''irreversible covalent''' - The stimulus is permanently bound to the target through irreversible chemical bond formation. |
Depending on the nature of the stimulus, the following can occur: | Depending on the nature of the stimulus, the following can occur: | ||
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* A conformational change in the target is induced by the stimulus which results in a change in target function. This change in function can mimic the effect of the endogenous substance in which case the effect is referred to as receptor agonism (or channel or enzyme activation) or be the opposite of the endogenous substance which in the case of receptors is referred to as inverse agonism | * A conformational change in the target is induced by the stimulus which results in a change in target function. This change in function can mimic the effect of the endogenous substance in which case the effect is referred to as receptor agonism (or channel or enzyme activation) or be the opposite of the endogenous substance which in the case of receptors is referred to as inverse agonism | ||
| - | + | == Common Drug targets== | |
The most common drug targets of currently marketed drugs include: | The most common drug targets of currently marketed drugs include: | ||
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* nuclear hormone receptors | * nuclear hormone receptors | ||
| - | + | ===Enzymes=== | |
| - | Enzymes are biomolecules that catalyze (i.e. increase the rates of) chemical reactions. Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products. Almost all processes in a biological cell need enzymes in order to occur at significant rates. Since enzymes are extremely selective for their substrates and speed up only a few reactions from among many possibilities, the set of enzymes made in a cell determines which metabolic pathways occur in that cell. | + | '''Enzymes''' are biomolecules that catalyze (i.e. increase the rates of) chemical reactions. Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products. Almost all processes in a biological cell need enzymes in order to occur at significant rates. Since enzymes are extremely selective for their substrates and speed up only a few reactions from among many possibilities, the set of enzymes made in a cell determines which metabolic pathways occur in that cell. |
Enzyme activity can be affected by other molecules. Inhibitors are molecules that decrease enzyme activity; activators are molecules that increase activity. Many drugs and poisons are enzyme inhibitors. Activity is also affected by temperature, chemical environment (e.g. pH), and the concentration of substrate. Some enzymes are used commercially, for example, in the synthesis of antibiotics. In addition, some household products use enzymes to speed up biochemical reactions (e.g., enzymes in biological washing powders break down protein or fat stains on clothes; enzymes in meat tenderizers break down proteins, making the meat easier to chew). | Enzyme activity can be affected by other molecules. Inhibitors are molecules that decrease enzyme activity; activators are molecules that increase activity. Many drugs and poisons are enzyme inhibitors. Activity is also affected by temperature, chemical environment (e.g. pH), and the concentration of substrate. Some enzymes are used commercially, for example, in the synthesis of antibiotics. In addition, some household products use enzymes to speed up biochemical reactions (e.g., enzymes in biological washing powders break down protein or fat stains on clothes; enzymes in meat tenderizers break down proteins, making the meat easier to chew). | ||
| - | + | ===Ligand-gated ion channels=== | |
The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are opened or closed in response to binding of a chemical messenger, as opposed to voltage-gated ion channels or stretch-activated ion channels. | The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are opened or closed in response to binding of a chemical messenger, as opposed to voltage-gated ion channels or stretch-activated ion channels. | ||
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The ion channel is regulated by a ligand and is usually very selective to one or more ions like Na+, K+, Ca2+, or Cl-. Such receptors located at synapses convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. | The ion channel is regulated by a ligand and is usually very selective to one or more ions like Na+, K+, Ca2+, or Cl-. Such receptors located at synapses convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. | ||
| - | Ligand-gated ion channels are likely to be the major site at which anaesthetic agents and ethanol have their effects, although unequivocal evidence of this is yet to be established. | + | Ligand-gated ion channels are likely to be the major site at which anaesthetic agents and ethanol have their effects, although unequivocal evidence of this is yet to be established. In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia. |
| - | + | Example: | |
| + | |||
| + | * nicotinic acetylcholine receptor | ||
| + | * GABA receptor | ||
| + | * ionotropic glutamate receptors | ||
| + | |||
| + | ===Voltage-gated ion channel=== | ||
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells. | Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells. | ||
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They have a crucial role in excitable neuronal and muscle tissues, allowing a rapid and co-ordinated depolarisation in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. | They have a crucial role in excitable neuronal and muscle tissues, allowing a rapid and co-ordinated depolarisation in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. | ||
| - | Examples | + | Examples: |
* the sodium and potassium voltage-gated channels of nerve and muscle. | * the sodium and potassium voltage-gated channels of nerve and muscle. | ||
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| - | + | ===G protein-coupled receptor=== | |
G protein-coupled receptors (GPCRs), also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. G protein-coupled receptors are found only in eukaryotes, including yeast, plants, choanoflagellates, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases, but are also the target of around half of all modern medicinal drugs. | G protein-coupled receptors (GPCRs), also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. G protein-coupled receptors are found only in eukaryotes, including yeast, plants, choanoflagellates, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases, but are also the target of around half of all modern medicinal drugs. | ||
| + | GPCRs can be grouped into 6 classes based on sequence homology and functional similarity: | ||
| - | + | * Class A (or 1) (Rhodopsin-like) | |
| + | * Class B (or 2) (Secretin receptor family) | ||
| + | * Class C (or 3) (Metabotropic glutamate/pheromone) | ||
| + | * Class D (or 4) (Fungal mating pheromone receptors) | ||
| + | * Class E (or 5) (Cyclic AMP receptors) | ||
| + | * Class F (or 6) (Frizzled/Smoothened | ||
| + | |||
| + | ===Nuclear hormone receptors=== | ||
In the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormones and certain other molecules. In response, these receptors work in concert with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism. | In the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormones and certain other molecules. In response, these receptors work in concert with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism. | ||
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors only happens when a ligand—a molecule which affects the receptor's behavior—is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor which in turn activates the receptor resulting in up-regulation of gene expression. | Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors only happens when a ligand—a molecule which affects the receptor's behavior—is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor which in turn activates the receptor resulting in up-regulation of gene expression. | ||
| + | |||
| + | Examples: | ||
| + | * Thyroid Hormone Receptor-like | ||
| + | * Retinoid X Receptor-like | ||
| + | * Estrogen Receptor-like | ||
| + | * Nerve Growth Factor IB-like | ||
| + | * Germ Cell Nuclear Factor-like | ||
| + | |||
| + | [[Category:Pharmacology]] | ||
| + | [[Category:Drug Discovery]] | ||
Current revision
The term biological target is frequently used in pharmaceutical research to describe the native protein in the body whose activity is modified by a drug resulting in a desirable therapeutic effect. In this context, the biological target is often referred to as a drug target.
Contents |
[edit] Drug targets Mechanism
The external stimulus (i.e., chemical substance) physically binds to the biological target.The interaction between the substance and the target may be:
- noncovalent
- reversible covalent - A chemical reaction occurs between the stimulus and target in which the stimulus becomes chemically bonded to the target, but the reverse reaction also readily occurs in which the bond can be broken.
- irreversible covalent - The stimulus is permanently bound to the target through irreversible chemical bond formation.
Depending on the nature of the stimulus, the following can occur:
- There is no direct change in the biological target, except that the binding of the substance prevents other endogenous substances such as activating hormone to bind to the target. Depending on the nature of the target, this effect is referred as receptor antagonism, enzyme inhibition, or ion channel blockade.
- A conformational change in the target is induced by the stimulus which results in a change in target function. This change in function can mimic the effect of the endogenous substance in which case the effect is referred to as receptor agonism (or channel or enzyme activation) or be the opposite of the endogenous substance which in the case of receptors is referred to as inverse agonism
[edit] Common Drug targets
The most common drug targets of currently marketed drugs include:
- enzymes
- ligand-gated ion channels
- voltage-gated ion channels
- G protein-coupled receptors
- nuclear hormone receptors
[edit] Enzymes
Enzymes are biomolecules that catalyze (i.e. increase the rates of) chemical reactions. Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products. Almost all processes in a biological cell need enzymes in order to occur at significant rates. Since enzymes are extremely selective for their substrates and speed up only a few reactions from among many possibilities, the set of enzymes made in a cell determines which metabolic pathways occur in that cell.
Enzyme activity can be affected by other molecules. Inhibitors are molecules that decrease enzyme activity; activators are molecules that increase activity. Many drugs and poisons are enzyme inhibitors. Activity is also affected by temperature, chemical environment (e.g. pH), and the concentration of substrate. Some enzymes are used commercially, for example, in the synthesis of antibiotics. In addition, some household products use enzymes to speed up biochemical reactions (e.g., enzymes in biological washing powders break down protein or fat stains on clothes; enzymes in meat tenderizers break down proteins, making the meat easier to chew).
[edit] Ligand-gated ion channels
The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are opened or closed in response to binding of a chemical messenger, as opposed to voltage-gated ion channels or stretch-activated ion channels.
The ion channel is regulated by a ligand and is usually very selective to one or more ions like Na+, K+, Ca2+, or Cl-. Such receptors located at synapses convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal.
Ligand-gated ion channels are likely to be the major site at which anaesthetic agents and ethanol have their effects, although unequivocal evidence of this is yet to be established. In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia.
Example:
- nicotinic acetylcholine receptor
- GABA receptor
- ionotropic glutamate receptors
[edit] Voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells.
They have a crucial role in excitable neuronal and muscle tissues, allowing a rapid and co-ordinated depolarisation in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals.
Examples:
- the sodium and potassium voltage-gated channels of nerve and muscle.
- the voltage-gated calcium channels that play a role in neurotransmitter release in pre-synaptic nerve endings.
[edit] G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. G protein-coupled receptors are found only in eukaryotes, including yeast, plants, choanoflagellates, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases, but are also the target of around half of all modern medicinal drugs. GPCRs can be grouped into 6 classes based on sequence homology and functional similarity:
- Class A (or 1) (Rhodopsin-like)
- Class B (or 2) (Secretin receptor family)
- Class C (or 3) (Metabotropic glutamate/pheromone)
- Class D (or 4) (Fungal mating pheromone receptors)
- Class E (or 5) (Cyclic AMP receptors)
- Class F (or 6) (Frizzled/Smoothened
[edit] Nuclear hormone receptors
In the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormones and certain other molecules. In response, these receptors work in concert with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors only happens when a ligand—a molecule which affects the receptor's behavior—is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor which in turn activates the receptor resulting in up-regulation of gene expression.
Examples:
- Thyroid Hormone Receptor-like
- Retinoid X Receptor-like
- Estrogen Receptor-like
- Nerve Growth Factor IB-like
- Germ Cell Nuclear Factor-like
