Drug targets Flashcards
explain DNA/RNA as a possible targets for drug binding
DNA and RNA are possible targets for drug binding because they play important roles in many cellular processes, such as gene expression, DNA replication, and protein synthesis. By interfering with these processes, drugs can have therapeutic effects in treating diseases such as cancer, viral infections, and genetic disorders.
For example, some drugs target DNA by intercalating, or inserting, between the base pairs of the DNA double helix, which can inhibit DNA replication and transcription. Other drugs target specific enzymes involved in DNA replication or repair, preventing the formation of new DNA strands or causing DNA damage.
Similarly, drugs can also target RNA by inhibiting its function in protein synthesis or RNA splicing, processes that are essential for cell growth and division. Some drugs target RNA viruses by interfering with their replication or translation processes.
Explain the structure and function of enzymes
The mechanism of action of a drug on an enzyme depends on its specific target and the biological process that it affects. Once the drug binds to the enzyme’s active site, it can alter the enzyme’s function in various ways. For example, it may inhibit the enzyme’s activity by blocking its active site, or it may activate the enzyme by inducing a conformational change in its structure.
The binding of a substrate to the active site of an enzyme is typically highly specific and selective, and it relies on the interaction of the substrate’s functional groups with the amino acid residues present in the active site. These interactions can be hydrogen bonding, electrostatic interactions, or van der Waals interactions, depending on the nature of the substrate and the active site.
explain Serine as nucleophile in catalysis, acid base catalysis
Serine is a common nucleophile in enzyme catalysis, especially in enzymes called serine proteases. Serine proteases are enzymes that cleave peptide bonds in proteins and are involved in a wide range of biological processes, including blood clotting, digestion, and immune response.
In serine proteases, the serine residue in the active site acts as a nucleophile by attacking the carbonyl carbon of the peptide bond that is being cleaved. This nucleophilic attack forms a covalent intermediate between the serine residue and the peptide substrate. This intermediate is stabilized by hydrogen bonding interactions with other amino acid residues in the active site of the enzyme.
Acid-base catalysis is another mechanism by which serine can act in enzyme catalysis. In acid-base catalysis, the serine residue acts as a proton donor or acceptor, facilitating the reaction by stabilizing reaction intermediates and transition states. For example, in serine proteases, the serine residue may act as an acid catalyst by donating a proton to the leaving group during peptide bond cleavage, or as a base catalyst by abstracting a proton from the incoming water molecule during hydrolysis of the covalent intermediate.
Transition State Inhibitors
Transition state inhibitors (TSIs) are a class of enzyme inhibitors that target the transition state of an enzymatic reaction. The transition state is a short-lived, high-energy state that occurs during a chemical reaction, where the reactants are partially converted into the products. TSIs are designed to mimic the transition state and bind to the enzyme with high affinity, thereby preventing the reaction from proceeding.
The specificity of TSIs arises from their ability to fit into the active site of the enzyme only when the substrate is in the transition state. This requires a high degree of complementarity between the inhibitor and the enzyme’s active site, and TSIs are typically designed to have a similar structure and charge distribution as the transition state of the enzymatic reaction.
TSIs have several advantages over other types of enzyme inhibitors. Because they bind to the transition state, which is typically a short-lived and highly unstable intermediate, they can be more specific and potent inhibitors than other types of inhibitors that target the enzyme’s substrate binding site. Additionally, TSIs often have higher selectivity for the enzyme target and lower toxicity, because they interact with the enzyme in a highly specific manner.
The development of TSIs is challenging, as they require detailed knowledge of the enzyme’s catalytic mechanism and the transition state of the reaction. However, TSIs have been successfully developed for several enzyme targets, including HIV protease, carbonic anhydrase, and metalloproteinases. They have also been explored as potential therapeutics for a wide range of diseases, including cancer, viral infections, and autoimmune disorders.
Reversible and Irreversible Inhibitors
Reversible inhibitors are molecules that bind to the enzyme and form non-covalent interactions, such as hydrogen bonds or van der Waals interactions. These interactions can be weak or strong, depending on the inhibitor and the enzyme, and can be disrupted by changes in temperature, pH, or concentration. Reversible inhibitors can be further classified into competitive, non-competitive, and uncompetitive inhibitors based on their mode of action.
Competitive inhibitors bind to the active site of the enzyme and compete with the substrate for binding. They typically have a similar structure to the substrate and can be overcome by increasing the substrate concentration.
Non-competitive inhibitors bind to a site on the enzyme that is not the active site, and their binding does not depend on the presence of the substrate. They often cause conformational changes in the enzyme that reduce its activity.
Uncompetitive inhibitors bind to the enzyme-substrate complex and prevent the release of the product. They often have a structure that is different from both the substrate and the enzyme.
In contrast, irreversible inhibitors bind to the enzyme and form covalent bonds with the enzyme, resulting in a permanent loss of enzymatic activity. This binding is typically irreversible and occurs at the active site or a nearby site on the enzyme. Irreversible inhibitors can be further classified into two types:
Suicide inhibitors, also known as mechanism-based inhibitors, are initially reversible inhibitors that form covalent bonds with the enzyme during the catalytic reaction, leading to irreversible inhibition. They often have a structure that mimics the substrate and undergoes a chemical transformation that generates a reactive intermediate that forms a covalent bond with the enzyme.
Allosteric inhibitors bind to a site on the enzyme that is not the active site and cause a conformational change that inhibits the enzyme’s activity. They are typically reversible, but their binding can be very strong and long-lasting.
Allosteric inhibitors can be either homotropic or heterotropic. Homotropic allosteric inhibitors are molecules that bind to the same site as the substrate, and their binding is affected by the concentration of the substrate. Heterotropic allosteric inhibitors, on the other hand, bind to a different site on the enzyme and their binding is not affected by the substrate concentration.
Mechanism of receptor function
Binding of ligand: Receptors are proteins that can recognize and bind specific ligands, which are molecules such as hormones, neurotransmitters, or drugs that can activate or modulate the activity of the receptor. When a ligand binds to the receptor, it can induce a conformational change in the receptor that can initiate downstream signaling events.
Receptor activation: The binding of the ligand to the receptor can activate the receptor by inducing a change in its shape or conformation. This can trigger a variety of intracellular signaling events that ultimately lead to a cellular response.
Signal transduction: Once the receptor is activated, it can initiate a series of signaling events inside the cell that can amplify and propagate the signal. This can involve the activation of intracellular signaling pathways, the release of second messengers, or the opening of ion channels.
Cellular response: The downstream signaling events triggered by the receptor activation can ultimately lead to a cellular response. This can include changes in gene expression, altered cellular metabolism, or modulation of ion channels and membrane potential.
Termination of signaling: The signaling initiated by the receptor can be terminated by a variety of mechanisms, such as receptor desensitization or degradation, the action of phosphatases or other negative regulators, or the removal of the ligand.
Agonists and Antagonists
Agonists
* Agonist binds reversibly to the binding site
* Similar intermolecular bonds formed as to natural messenger
* Induced fit alters the shape of the receptor in the same way as the normal messenger
* Receptor is activated
* Agonists are often similar in structure to the natural
messenger
Antagonists:
Antagonists can bind to a receptor and prevent the binding of an agonist or block the receptor from initiating downstream signaling events. This can lead to inhibition of the receptor’s activity and a decrease in cellular response. Antagonists are used as drugs in a variety of contexts, such as in the treatment of hypertension or in the prevention of drug abuse. An example of an antagonist is naloxone, which can bind to the same receptor as morphine and block its activity.
There are two types of antagonists:
Competitive antagonists: These are molecules that bind to the same site on the receptor as the agonist and compete with it for binding. The strength of the antagonist is proportional to its concentration, and increasing the concentration of the antagonist can reduce the effect of the agonist.
Non-competitive antagonists: These are molecules that bind to a different site on the receptor than the agonist and inhibit its activity without competing for binding. Non-competitive antagonists can reduce the efficacy of an agonist even at high concentrations.
Explain Signal transduction
Reception: Extracellular signaling molecules such as hormones, neurotransmitters, or growth factors bind to specific receptors located on the surface of the cell membrane. The binding of the signaling molecule to the receptor causes a conformational change in the receptor that activates it.
Transduction: The activated receptor triggers a series of biochemical events or signaling pathways that transmit the signal from the cell membrane to the nucleus or other cellular compartments. This process involves the activation of intracellular signaling molecules such as G proteins, enzymes, and second messengers that amplify and propagate the signal.
Amplification: The signaling cascade amplifies the initial signal, which allows the cell to respond to small amounts of signaling molecules. Amplification also allows the cell to achieve specificity in response to different signals.
Modulation: The signal is modulated by various mechanisms to control the intensity, duration, and location of the response. For instance, the signal may be amplified or inhibited by feedback loops, cross-talk with other signaling pathways, or post-translational modifications.
Response: The signal transduction pathway ultimately leads to a cellular response, which may include changes in gene expression, alterations in enzyme activity, cell migration, or cell proliferation. The response can be immediate or delayed, depending on the signaling pathway and the downstream effectors.
Termination: The signal transduction pathway is terminated by various mechanisms, including degradation of the signaling molecule, deactivation of the receptor, or removal of second messengers. This ensures that the cell response is transient and does not become chronic or pathological.
Signal transduction on ion channels
Receptor activation: Extracellular signals such as neurotransmitters, hormones, or growth factors bind to specific receptors on the cell membrane, which activate intracellular signaling pathways.
Activation of intracellular signaling pathways: The activation of receptors triggers the activation of intracellular signaling pathways such as G protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs). These pathways can activate downstream signaling molecules such as second messengers, protein kinases, or phosphatases.
Modulation of ion channels: The downstream signaling molecules can directly or indirectly modulate the activity of ion channels by various mechanisms, such as phosphorylation, dephosphorylation, or direct interaction with the ion channel protein. For example, the phosphorylation of ion channels by protein kinases can increase or decrease their activity, while dephosphorylation can have the opposite effect.
Alteration of ion flux: The modulation of ion channels by signaling pathways can alter the flux of ions across the cell membrane, leading to changes in membrane potential, intracellular calcium concentration, or ion homeostasis. These changes can have various effects on cell function and behavior, such as changes in neurotransmitter release, muscle contraction, or gene expression.
Termination of signaling: The signaling pathway is terminated by various mechanisms, including receptor desensitization, degradation of second messengers, or termination of phosphorylation/dephosphorylation cascades. This ensures that the cellular response to the signal is transient and does not become chronic or pathological.
Intracellular receptors
Ligand binding: Intracellular receptors are activated by the binding of specific signaling molecules, typically lipophilic or hydrophobic molecules that can cross the cell membrane. Examples of ligands that bind to intracellular receptors include steroid hormones, thyroid hormones, and retinoids.
Allosteric sites
Allosteric sites: Proteins have specific sites, called allosteric sites, that are distinct from their active sites. These sites can bind to specific molecules, called allosteric modulators, that can either activate or inhibit protein activity.
Conformational change: When an allosteric modulator binds to the allosteric site, it induces a conformational change in the protein, which can either increase or decrease its activity. This conformational change can alter the protein’s active site, its ability to bind to other molecules, or its interactions with other proteins.
Cooperative binding: In some cases, the binding of an allosteric modulator can induce a cooperative effect, in which the binding of one modulator molecule increases the affinity of the protein for subsequent molecules. This can amplify the effects of allosteric control and enable a rapid and sensitive response to changes in cellular conditions.
Specificity: Allosteric control is highly specific, as allosteric modulators bind to specific allosteric sites on the protein that have a unique shape and chemical composition that matches the modulator’s structure. This specificity enables the selective regulation of protein function and minimizes unintended effects on other cellular processes.
Reversibility: Allosteric control is reversible, as the binding of allosteric modulators to the protein is typically weak and can be disrupted by changes in cellular conditions or the presence of other molecules.
