Molecular Targets Flashcards
What is a receptor?
A receptor is a target molecule through which soluble physiological mediators produce biological effects.
What is the structure of a GPCR?
GPCRs have seven transmembrane domains and are coupled to G proteins to initiate signal transduction.
Why are GPCRs significant as drug targets?
GPCRs represent over 50% of current drug targets, with 800 genes (400 non-olfactory genes).
Name some examples of GPCR-targeted drugs.
• Ranitidine for stomach ulcers (Histamine H2 receptor).
• Loratadine for allergies (Histamine H1 receptor).
• Atenolol for hypertension (β-adrenoreceptor).
How are GPCRs classified?
Based on sequence homology:
• Class A: Rhodopsin-like.
• Class B: Secretin-like.
• Class C: Metabotropic glutamate/pheromone.
• Classes D-F: Various other types.
Describe the steps of GPCR activation.
- Agonist binds to GPCR.
- Receptor shape changes, exposing binding sites.
- G protein couples to receptor.
- GDP is exchanged for GTP.
- G protein subunits separate, activating signaling pathways.
What is GPCR desensitization?
• A rapid mechanism to prevent continuous activation.
• Achieved through phosphorylation or internalization.
• Two types:
• Homologous (specific receptor).
• Heterologous (affects shared signaling cascade receptors).
What is the difference between desensitization, degradation, and tolerance?
• Desensitization: Rapid prevention of receptor signaling.
• Degradation: Receptor removal via lysosomes.
• Tolerance: Reduced drug efficacy over time.
What is biased agonism in GPCRs?
Biased agonism occurs when different agonists induce unique receptor conformations, favoring specific signaling pathways.
What are nuclear receptors?
Ligand-activated transcription factors with three domains:
• Ligand-binding.
• DNA-binding.
• Transcription-activating.
How do nuclear receptors function/activate?
- Ligands diffuse into cells.
- Bind to ligand-binding domains.
- Receptors dimerize and translocate to the nucleus.
- Bind DNA to alter gene expression.
Name some drugs targeting nuclear receptors and their uses.
• Dexamethasone: Anti-inflammatory, immunosuppressant.
• Tamoxifen: Estrogen receptor antagonist for breast cancer.
How are nuclear receptor agonists transported in the body?
By carrier proteins like thyroxine-binding globulin and sex hormone-binding globulin.
How does tamoxifen act as both an antagonist and agonist
Agonist: Acts in tissues with high co-activator concentrations.
Antagonist: Acts in breast tissue with high co-repressor concentrations.
Tamoxifen is a selective estrogen-receptor modulator (SERM).
What are ion channels, and why are they important as drug targets?
Ion channels are membrane proteins that allow ions to pass through the cell membrane, following their electrochemical gradients. They regulate processes such as nerve signal transmission, muscle contraction, and hormone secretion. Ion channels are targeted by drugs to treat arrhythmias, epilepsy, and hypertension.
What are the main types of voltage-gated ion channels, and how do they function? Examples of drugs too
- Potassium channels (K+): Regulate action potential shape and membrane potential. Example: Minoxidil opens K+ channels for hypertension.
- Sodium channels (Na+): Involved in generating action potentials. Example: Lidocaine blocks Na+ channels to treat arrhythmias.
- Calcium channels (Ca2+): Mediate neurotransmitter release and muscle contraction. Example: Verapamil blocks L-type Ca2+ channels for hypertension and angina.
What are channelopathies? Provide examples.
Channelopathies are diseases caused by malfunctioning ion channels. Examples: Epilepsy: Malfunction of Na+ or K+ channels. Ataxia: Impaired Ca2+ channels. Diabetes: Defective KATP channels.
How do ligand-gated ion channels (LGICs) differ from voltage-gated ion channels?
Ligand-gated channels: Open in response to a specific molecule binding (e.g., neurotransmitters). Example: GABAA channels open when GABA binds. Voltage-gated channels: Open in response to changes in membrane potential.
Name key LGICs and their therapeutic targets.
- nACh Receptors (Nicotinic): Succinylcholine acts as a full agonist, used for short-term neuromuscular blockage during surgery.
- GABAA Receptors: Diazepam enhances inhibitory action, used for anxiety and epilepsy.
- 5-HT3 Receptors: Granisetron blocks these to reduce nausea during chemotherapy.
- NMDA Receptors: Memantine inhibits overstimulation in Alzheimer’s disease.
What are transporters, and what role do they play as drug targets?
Transporters are proteins that move molecules across cell membranes. They are essential for nutrient absorption, neurotransmitter recycling, and ion balance. They are targeted by drugs to treat diseases such as depression and amyotrophic lateral sclerosis (ALS).
What are the key transporter mechanisms?
- Passive diffusion: No protein or energy required (e.g., glycerol). 2. Facilitated diffusion: Protein required; no energy (e.g., glucose transporters). 3. Primary active transport: Energy from ATP hydrolysis (e.g., Na+/K+ ATPase). 4. Secondary active transport: Energy indirectly from ion gradients (e.g., sodium/glucose symport).
Give examples of drugs targeting transporters.
- SERT (Serotonin transporter): Targeted by SSRIs like citalopram for depression.
- DAT (Dopamine transporter): Blocked by dexamfetamine for ADHD.
- EAAT (Glutamate transporter): Riluzole increases uptake to manage ALS.
What are enzyme-coupled receptors, and how do they work?
ECRs are membrane receptors linked to intracellular enzymes. Ligand binding causes receptor dimerization and autophosphorylation of intracellular domains, activating signaling cascades that regulate cell proliferation, metabolism, and survival.
What are examples of ECRs and their roles?
- Receptor tyrosine kinases: Regulate growth and metabolism (e.g., insulin receptor). 2. Receptor serine/threonine kinases: Mediate TGF-β signaling. 3. Receptor guanylyl cyclases: Produce cGMP as a second messenger.
How do tyrosine kinase inhibitors (TKIs) work? Example of drug
TKIs block phosphorylation by receptor tyrosine kinases, inhibiting cancer cell proliferation.
Examples: Imatinib: Blocks Bcr-Abl kinase in leukemia.
Sorafenib: Targets VEGF receptor for kidney and liver cancers.
How do enzymes function, and why are they targeted by drugs? Examples of drugs
Enzymes catalyze biochemical reactions by lowering activation energy. Drugs target enzymes to alter reaction rates, often by inhibiting enzyme activity.
Examples: 1. Competitive inhibitors: Bind the active site (e.g., penicillin inhibits bacterial DD transpeptidases).
2. Non-competitive inhibitors: Bind allosteric sites (e.g., aspirin inhibits cyclooxygenase to reduce inflammation).
What are examples of enzyme-targeting drugs?
- Penicillin: Inhibits bacterial cell wall synthesis.
- Aspirin: Reduces prostaglandin synthesis, easing pain and inflammation.
- ACE inhibitors (e.g., ramipril): Lower blood pressure by inhibiting angiotensin II production.
Why are molecular targets important in drug discovery?
Understanding molecular targets like ion channels, transporters, and enzymes enables the development of precise therapies for diseases like cancer, depression, and epilepsy. Advances in molecular biology and pharmacology help identify novel drug targets and mechanisms.
