L3: Drug Targets, identification, and validation Flashcards
what are drug targets
a protein that drugs act upon – the drug changes the shape and thus function of the protein.
why are other macromolecules not good drug targets
- DNA and RNA – hard to find potent compounds
- Lipids (fats) – low specificity
- Carbohydrates (sugars/starches) – toxicity
what are the main types of drug targets for current drugs ( 2 types)
- Enzymes (protein machines that do work)
- Receptors (proteins involved in communicating a signal)
what do drugs look like when they interact with receptors and enzymes. use two respective examples
ex.
receptors
- the opioid receptor makes a pocket for the opioid drug on the plasma membrane
enzyme (ends with -ase)
- weight loss drug and its protein target is pancreatic lipase which is also in a pocket of the enzyme
explain enzyme and substrate mechanism (lock and key/induced fit)
substrates approach an enzyme’s active or catalytic site.
the substrates bind (enzyme changes shape to fit) and undergo a chemical reaction creating the products which are released from the enzyme-substrate/product complex as they dont fit as well.
explain how receptors works and its ligand
- Type of protein
- Involved in cell communication – relays information
- Found on surface or inside of cell
- Bind to chemical messengers called ligands (can be hormones)
- Relay the message to the cell
- Cell reacts by functioning differently
- Many hormone effects are mediated by receptors
what are the 5 types of recpeptors
- ligand/drug enters fully into the cell and binds to the receptor inside
- ligand/drug binds to the receptor outside the cell, and the product is created inside the cell as a reaction
- ligand approaches receptor on the membrane and an enzyme fits the inside of the receptor thus creating a product
- ion channel – ligand approaches the membrane and receptor and changes shape to pass through inside the cell, sending a signal inside the cell
- ligand approaches the receptor and causes the receptor to shift along the membrane binding to another receptor, creating a product
explain cell signaling
a chain of molecular events producing a communication inside the cell
hormone or environmental stimulus binds with receptor (reception) -> reaction is produced with secondary messengers (signal transduction)
-> an activation of cellular processes (response)
what is a drug-receptor complex
drug + receptor = DR complex –> produces an effect
what are pharmacodynamics?
what are normal and altered physiological responses?
pharmacodynamics: interaction with cellular targets
normal:
ligand approaches receptor and forms a normal physiological response (active)
altered:
drug covers the active site of the receptor so the ligand cannot bind. the bindment of the drug creates an altered physiological response –> this is the point of drugs
what is target identification and its premise
target identification: determining possible drug targets for drugs of the future.
premise to target identification:
*A macromolecule (usually a protein) exists that is central to the disease mechanism - drug target exists
* If we modulate this protein with a drug we will improve the health status of the patient
what is the difference between genomics and genetics
- Genomics: study of all the genes in the genome
and the interactions among them and their environment
*Genetics: study of single genes in isolation
why do we use genomes instead of protiens to identify targets
While drug targets are usually proteins, we use genomes to identify targets, due to the lower complexity of the genome
one way to finding targets – how do we find which genes/proteins are different between healthy people and those with disease?
Genome-wide association studies
- evaluate chromosomes of controls and patients, and identify which proteins/genes differ
explain the example of target identification by correlations study of the cancer genome
what is a con of this method
what is target validation
Cancer Genome Changes reveal possible drug targets (pathways): target identification
- con: there are too many possible targets identified. Cannot make a drug for each
- target validation:
which is the actual protein target that affects the mechanism of the disease – because not all that were found actually effect the disease to a large effect. how do we find if its worth developing a drug against all, lets say, 200 of these changes.
