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218 Cards in this Set
- Front
- Back
What is potency?
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How strongly the drug molecule interacts with its intended target
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What is selectivity?
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A measure of how much more strongly the compound interacts with the target compared to other targets
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What is efficacy?
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How effective the compound functions in the patient. High potency and selectivity do not guarantee high efficacy.
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What is the most common drug target?
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Protein
Receptors and Enzymes have nice binding sites It's hard to bind nucleic acids, they mostly look the same |
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What is a Natural Product?
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Compound isolated from a natural source (usually plants) and used in an unchanged form
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What is a semisynthetic drug?
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A natural product that's slightly modified through chemical reactions to produce a non-natural drug.
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What is a synthetic drug?
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A drug where the majority of the structure is created through chemical reactions from commodity chemicals
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What are characteristics of natural product drugs?
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They have more stereochemistry and general look more complex.
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What is discovery chemistry?
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Drug target is unknown
Small scale synthesis Speed is key Make a lot of compounds |
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What is process chemistry?
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Target is known
Kilo-ton scale is typical Efficiency is key Has to be efficient and high yield |
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How many cells are in the human body?
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About 3 x 10^13
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What is Avogadro's number?
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6.02 x 10^23
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What is pharmacodynamics?
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What the drug does to the body
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What is pharmacokinetics?
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What the body does to the drug
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ADME is determined by _________________.
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the structure of the drug / variations in human body
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In vitro studies ...
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the action of the drug candidate on the molecular target - efficacy and selectivity
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In vivo studies ...
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look at pharmacology kinetics and dynamics, toxicity, side effects
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What is an IND?
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Investigational New Drug
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What is a commercial IND?
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typically submitted by drug manufacturer companies to market a new product
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What is a treatment IND?
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special case for serious illness (cancer, Alzheimers, HIV) and only needs preliminary evidence of drug efficacy
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What is emergency use IND?
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Drugs for life threatening situations, no standard form of treatment so insufficient time for a regular IND application
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Who participates in a Phase I clinical study?
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About 20-80 patients, all healthy individuals
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What does a Phase I clinical trial study?
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primarily for safety, establish pharmacokinetic and metabolism studies, establish maximum tolerated dose, look for unexpected adverse effects
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Who participates in a Phase II clinical study?
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About 100-300 patients in the targeted disease population
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What does a Phase II clinical trial study?
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Establish maximal and minimal effective dose, establish maximal safe dose, PK in the disease population, adverse effects
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Who participates in a Phase III clinical study?
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About 1000 patients, two randomized groups (placebo), double blinded with a switchover
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What does a Phase III clinical trial study?
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Conclusive evidence that a new drug is safe and effective
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What is an NDA?
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New Drug Application
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What is included in an NDA?
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Data that shows:
Drug is safe and effective for proposed indication Benefits of drug outweighs the risks Labeling is sufficient Methods of manufacturing and quality control |
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What is Phase IV clinical study?
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Marketing and followup study
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What percent of drugs display side effects not seen prior to approval?
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More than 50%
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What fraction of drugs is subject to a dose reduction after approval?
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1 in 5
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What fraction of drugs is actually profitable? o.o
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1 out of 3
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How long does drug discovery take?
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3.5-6.5 years
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How long do clinical trials take?
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3.5 years
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Which phase of clinical trial is the most expensive?
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Phase III
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What is the most common reason for IND termination?
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Low efficacy
(then safety, then economic) |
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What is a blockbuster drug?
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Compounds that make more than 1 billion in revenue
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Which elements commonly appear in drug molecules?
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C H N O P S Br Cl I B
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How big are synthetic drugs usually?
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MW 200-500
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Why do a lot of drug molecules have cyclo structures?
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To get around stereochemistry issues
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Describe the scaffold model.
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Central scaffold - common structure
Functional groups - things around the central scaffold |
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Carbon can appear in three different hybridization states, what are they?
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sp3 - tetravalent
sp2 - trivalent sp - divalent |
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What is the approximate energy difference between cis and trans?
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60kcal/mol
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What are enantiomers?
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Non-superimposable mirror images.
They have the same chemical/physical properties but not the same biological properties. |
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What are diastereomers?
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Non-superimposable non-mirror images. (but still isomers)
They don't have the same chemical/physical properties and they're completely different compounds. |
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How many diastereomers/enantiomers are there for a molecule with n stereocenters?
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2^n
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D/L
Which form of amino acids and nucleic acids do we use in our bodies? |
L-amino acids and D-nucleic acids
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What does dextro and levo refer to?
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Rotation of light - dextro is +, levo is -
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What are the eutomer and distomer?
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Enantiomers, the more active one is the eutomer, the less active one is the distomer.
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What is the eudismic ratio?
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Ratio of the eutomer and distomer (in terms of activity?)
The more potent the eutomer is, the higher the eudismic ratio. (The distomer doesn't get worse as the eutomer gets better) |
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What are conformational isomers?
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Isomers that are a single compound, but with rotated bonds or inverted rings.
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What is the Boltzmann distribution?
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The distribution of the conformational isomers in terms of energy. If the energy for the bioactive form is too high, there might not be enough of it to be effective.
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When pH = pKa, how much of the solution is ionized?
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50%
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What is bulk flow transfer?
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Rapid distribution of the drug through the cardiovascular system, independent of the drug structure
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What is diffusional transfer?
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Transfer of molecules across a barrier, dependent of the drug structure.
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What is the significance of logP?
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Measure of hydrophilicity/lipophilicity. Drugs have to be both to diffuse through the body.
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What ratio is logP?
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Concentration of drug in an organic solvent/concentration of drug in an aqueous solvent.
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What are Π values?
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logP values for specific side groups, like -CH3. They are additive.
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What logP value denotes water solubility?
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logP < 0.5 is water soluble (at least 3.3% solubility)
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What is the Π value of a phenyl group?
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+2
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What is the Π value of heteroatoms?
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mostly negative
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What is the Π value of a CH3 or CH2 group?
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+0.5
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What is logD used for?
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It's like the logP value, but for ions.
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What values do you need to determine logD?
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pKa of ionizing group
pH partition values |
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What is clearance?
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Rate of removal of a drug from the body
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What is the volume of distribution?
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A theoretical volume into which a drug is disseminated
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What is bioavailability?
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The fraction of administered dose that actually reaches the systemic circulation
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What is the half life?
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The amount of time it takes to reduce the drug concentration by 50%
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What is Lipinski's rule of 5?
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More than 5 hydrogen donors
More than 10 hydrogen acceptors Molecular weight above 500g/mol logP greater than 5 if the drug meets two of these, it's unlikely to be an orally active drug molecule |
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What is Kd?
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koff/kon
[receptor][ligand]/[receptor:ligand] as drug binds better, the Kd decreases |
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What is the thermodynamic equation for binding?
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deltaG = -RTlnKeq = RTlnKd
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Your friendly standard thermodynamics equation
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deltaG = deltaH - TdeltaS
H - enthalpy T - temperature in Kelvin S - entropy |
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What are non-covalent interactions?
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Weak interactions between molecules that are responsible for stability and binding affinity
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Non-covalent interactions are exo or endo thermic?
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Exothermic
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A higher boiling point indicates stronger or weaker attractive forces?
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Stronger
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What are Van der Waals interactions?
(London Dispersion Forces) |
Weakest interactions, dependent on distance, creates induced dipole, contributes about -0.5 kcal/mol
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What is the Lennard-Jones potential?
(6-12) |
Energy of VDW interactions, 12 is repulsive, 6 is attractive
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What noncovalent interaction is most important between two hydrophobic groups?
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Van der Waals / London Dispersion Forces
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As alkanes get (bigger/smaller) there are more VDW interactions.
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bigger
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Pi stacking occurs with __________.
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Co-planar aromatic groups
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What are charge transfer complexes?
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Interaction formed between an electron donor and an electron acceptor.
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How much energy does a charge transfer complex account for?
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-1 to -7 kcal/mol
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What are ion/dipole and dipole/dipole interactions?
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They're like permanent VDWs, strong and fairly common.
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How much energy do ion/dipole and dipole/dipole interactions account for?
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-3 to -5 kcal/mol
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What are hydrogen bonds?
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Uh.. hydrogen bonds. LOL
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How much energy do hydrogen bonds account for?
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-3 to -5 kcal/mol
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What are electrostatic interactions?
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Interactions formed between two formally charged groups (ions), one of the strongest interactions
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How much energy do electrostatic/ionic interactions account for?
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-5 to -10 kcal/mol
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What is strain energy?
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When the conformation state is different from the ground state, there's an energy penalty (up to 10kcal/mol)
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What are steric interactions?
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VDWs gone wrong. They're too close together.
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What does bulk water have to do with binding?
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When two things bind/interact, there's a loss of entropy there, but the water molecules that were around the two things are returned to bulk water which conpensates.
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When a drug is bound to the target, how much rotational energy is lost?
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14 kcal/mol, may be lower if there's movement in the binding site
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The key reaction is between (electrophilic/necleophilic) sites on the drug molecule and (electrophilic/nucleophilic) sites on the drug target.
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Electrophilic on drug molecule
Nucleophilic on drug target |
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Electrophiles would be bad 'cause they like to bind to ________.
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DNA (lol)
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What is a pharmacophore?
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The groups on the molecule that directly interact with the receptor.
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What are the parts of the drug molecule that don't interact with the receptor/target called?
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Auxophores
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Do common scaffolds predict a common target?
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Sort of but not really.
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Alkanes, go.
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
VDWs interactions
Hydrophobic Oxidized by cytochromes No acid/base Low chemical reactivity |
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How much does each carbon (in alkanes) add to the logP?
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+0.5
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What are common ring sizes in drugs?
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5 and 6
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The thing in poison ivy that makes you itchy is a small molecule. Antibodies don't bind small molecules. Why are you still itchy?
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The small molecule binds to a surface protein or something in your body and that complex is large enough to be targetted by antibodies.
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Benzenoid Aromatics, go.
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
VDWs, Pi stacking
Hydrophobic Oxidation by cytochromes to phenols No acid/base Low, they're stable |
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Alcohols, go
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Hydrogen bond donors/acceptors
Hydrophilic Oxidation or Conjugation Slightly acidic React as nucleophiles |
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How is the "degree" of an alcohol group determined?
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Primary alcohols are attached to carbons attached to one other carbon.
Secondary alcohols are attached to carbons attached to two other carbons, etc. |
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Phenols are (more/less) acidic than alcohols?
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More acidic
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Amines, go.
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Hydrogen bond acceptor/donor
Hydrophilic Oxidation with Deamination Weak base React as nucleophiles |
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Ethers and Acetals, go
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
H bond acceptor, dipole interactions
Slightly hydrophilic Not much No acid/base Notreally |
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What are epoxides?
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Those triangle things with Oxygen in them. Highly strained (35kcal/mol), electrophilic
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Carbonyl stuff, go
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Hydrogen bond acceptors, VDW, dipole dipole
Hydrophilic Reduction and hydrolysis Slighly basic at oxygen but not really ionized Reactive toward nucleophiles, they act as electrophiles |
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Which carbonyl groups will you never see in drugs?
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Acid chloride (RCOCl)
Anhydrides (RCOOCOR') Aldehydes are rare. (RCHO) |
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In a C=O double bond, which is electrophilic and which is nucleophilic?
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O is nucleophilic, C is electrophilic
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What are lactones?
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Cyclic esters.
5 - butyrolactone 6 - valerolactone 7 - caprolactone |
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Esters can undergo hydrolysis to release a ___________ or ___________.
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alcohol or carboxylic acid
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What is an amide?
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Compound with acyl group (RC=O) linked to N
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What are primary, secondary, tertiary amides?
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Primary - one carbon attached to Nitrogen
Secondary - two carbons attached to Nitrogen Tertiary - three carbons attached to Nitrogen |
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What are lactams?
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Cyclic amides.
Size denoted by Greek symbols Alpha = 3 Beta = 4 |
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Amides can act as hydrogen acceptors. Where does the hydrogen bond?
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on the doublebonded Oxygen, not the Nitrogen
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What is a carbonate?
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RO(C=O)OR'
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What is a carbamate (urethane)?
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RR'N(C=O)OR''
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What is urea?
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RR'N(C=O)NR''R'''
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Carboxylic Acids, go
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Hydrogen bond acceptor/donor, ionic interactions
Greatly hydrophilic Phase II glucoronidation Weak Acid Nucleophile |
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What is an imine?
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R(C=NR'')R''
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What is an amidine?
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R(C=NH)R'
|
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What is a guanadine?
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R-NH(C=NH)NH2
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What are nitriles?
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-C≡N:
Stable, linear, low basicity |
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Heteroaromatics, go
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Similar to amines, hydrogen bond acceptor/donor
Hydrophilic Complex, ring oxidation Weakly basic Some |
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Draw pyridine and pyrimidine and pyrrole and imidazole and indole.
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Pyridine - Benzene but one N
Pyrimidine - Benzene but two Ns CCNCNC Pyrrole - aromatic Pentagon with NH Imidazole - Pyrrole with another N in the ring |
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What are the rules of aromaticity?
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1. Planar
2. Full conjugation 3. 4n+2 electrons |
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Halogens, go.
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Weak Hydrogen bonds on lone pairs, hydrophobic interactions
Hydrophobic Reductive dehalogenation No acid/base Alkyl halides can react as electrophiles |
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What's so special about Fluorine?
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It has about the same size as H and often used to substitute Hydrogens that are metabolized readily to increase the half life.
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Aryl halides are (reactive, nonreactive).
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They're generally stable and nonreactive.
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Aliphatic halides are (reactive, nonreactive).
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Reactive, they're prone to nucleophilic substitution.
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Which Alkyl halide is the most stable?
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Alkyl fluoride
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Sulfoxide/Sulfones/Sulfonamides, go
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Strong dipole interactions
Hydrophilic Little metabolism No acid/base Very stable |
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What is sulfoxide?
|
R(:S=O)R
|
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What is sulfone?
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R(O=S=O)R
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What is sulfonamide?
|
R(O=S=O)NR'R''
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What are cool about sulfonamides?
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They mimic transition state molecules.
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Sulfonic acid/Sulfate go
Key Interactions Role on Solubility Metabolism Significant Acid-Base Chemical reactivity |
Strong ionic interactions
Hydrophilic Little metabolism No acid/base Very stable |
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What's the difference between a phosphonate and a phosphate?
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Phosphonates don't have the oxygen next to the R group
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Sulfides are susceptible to which kind of reaction?
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Oxidation
|
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Thiols are unstable why?
|
They create disulfide bridges lol
Oxidation in the air |
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What makes a good drug target?
|
Target is essential to the path in question
Function is not duplicated by an alternative path Has a druggable structure, where small molecules can bind Target is accessible to these small molecules from the bloodstream |
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Proteins have several degrees of structure; how many and what are they?
|
Primary - amino acid sequence
Secondary - Alpha helices and beta sheets Tertiary - three dimensional structure, disulfide bridges? Quaternary - More than one polypeptide in the protein complex |
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Amino acids are linked through which type of bond?
|
Amide bonds or Peptide bonds
|
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What is the simplest amino acid?
|
Glycine lol
|
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Which amino acid residues ionize around physiological pH? Hint: There are five of 'em.
|
Aspartic Acid
Glutamic Acid Lysine Arginine Histidine |
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Which amino acids are amphipathic?
|
Tyrosine
Lysine Tryptophan Methionine |
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How many residues are in each turn of the alpha helix?
|
About 4?
|
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In alpha helix, do the residues go inwards or outwards?
|
They project out from the helix
|
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What is tubulin?
|
A structural protein crucial to cell division. The microtubules depolymerize give tubulin and repolymerized into the spindle thingy.
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What is the difference between A and B DNA?
|
B DNA has the central axis in the middle of the base and A DNA has them rotating around the central axis but not necessarily in the middle of the base.
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What is fractional occupancy?
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[ligand:receptor]/
[ligand:receptor]+[receptor] or [ligand]/ [ligand]+Kd |
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What is Bmax?
|
Total number of target binding sites
|
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What is the IC50?
|
Concentration of a (new) drug that blocks 50% of the binding of the standard.
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What is the EC50?
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The concentration of drug that produces half of the maximal effect.
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How do statins work?
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They resemble the transition state of HMG-CoA and bind to the enzyme.
|
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How does penicillin work?
|
It looks like D-ala which bacteria use in the peptidoglycan layer.
|
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What is the first step of drug discovery?
|
Choosing a disease
Then picking a target Identify a lead compound Identify pharmacophore |
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What is target identification?
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Identification of (a) biomolecule(s) or signaling pathway that plays a role in the disease development or progression
|
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Describe the target based drug discovery process.
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Target identification, target validation, Assay development, lead identification, lead optimization, development
|
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What are some considerations regarding target selection?
|
Has to be selective for the species and unique to the pathogen/target
Think bacteria vs human, or the differences between the different types of dopamine receptors |
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What are the most common drug targets?
|
Receptors, Enzymes, Hormones
|
|
What is affinity purification?
|
Running the ligand and proteins through a bead column and seeing what elutes lol I dunno.
|
|
What is proteomics?
|
Comparison of total protein levels and markers
|
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What is genomics?
|
Comparison of genomic DNA levels and markers
|
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What is chemogenomics?
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Using a small molecule or known drug which causes a disease relevant phenotype either in vivo or in vitro and using it to identify the cellular targets.
|
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What is toxicogenomics?
|
Predict how a given cell, tissue, organ, individual will respond to a certain toxic substances.
|
|
What is pharmacogenomics?
|
Study of how an individual's genes affects his/her response to a drug.
|
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What is cDNA?
|
Complementary DNA, made from reverse transcriptase and mRNA strands. It has the protein encoding part of the gene and no introns.
|
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What is the difference between genetics and genomics?
|
Genomics is the entire genome, genetics focuses on specific genes.
|
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What are DNA microarrays used for?
|
Comparing the levels of certain cDNA in two different states (like control vs experimental). The strands are tagged with colors and the overexpression is determined by the color in the well.
|
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What are some issues with studying proteomics?
|
Sometimes the protein can't be purified, like if it's a membrane protein or if it's charged.
There's no way to amplify a protein, like DNA there's PCR, but for proteins there isn't any technique like that. There's no way to determine post translational modification or to mimic those thingies, like glycosylation and such. |
|
Explain protein microarrays.
|
They're sort of like DNA microarrays, labelled with dye and put into specific wells. The chip is loaded with antibodies rather than mRNA and they bind to specific proteins. The colors determine the level of proteins present in the two different states.
|
|
What are some target validation strategies?
|
Antisense
Zinc Finger Proteins Knockout Mice Recombinant Protein Microarray |
|
What is antisense technology?
|
Creating RNA or DNA oligonucleotides to be complementary to a known mRNA sequence, so the oligonucleotide binds to the mRNA and the protein synthesis is shut off and we can see the effects of that gene being turned off/protein being missing.
|
|
What is microRNA (miRNA)?
|
Short RNA sequences made to silence gene transcription. They work with RISC - RNA silencing complex to prevent protein expression. mRNA cleavage and translation inhibition
|
|
What is RNAi?
|
RNA interference rawr
|
|
What are zinc finger proteins?
|
Proteins that bind DNA and regulate the expression of the gene
(They have zinc in them to stabilize their structure) |
|
What is comparative genomics?
|
Study of relationships between genome structure and function across different species
|
|
What are knockout mice?
|
Mice that are genetically engineered to have a specific gene turned off. They have two nonfunctioning copies of the gene.
|
|
What source do most FDA approved drugs come from?
|
Synthetic, then Natural Product derived
|
|
What is high throughput screening?
|
Technology that allows for rapid evaulation of large quantities of compounds in different bioassays to identify potential therapeutic agents.
|
|
What tradeoffs exist between well plate sizes?
|
Plates with more wells have less volume so they're less sensitive, but it costs less 'cause you don't have to put as much into each well.
|
|
What is a biochemical assay?
|
Screening for compounds that interact with an isolated target in an artificial environment.
|
|
What is a cell based assay?
|
Analyzing a measurable effect of a given target within a cell in its natural environment.
|
|
Biochemical assays can be __________ or ___________ .
|
Analytical ; Functional
|
|
Cell based assays can be ___________ or ___________ .
|
Natural or Reporter Gene
|
|
How does the dual luciferase assay system work?
|
Renilla is the control, it should always be active. Firefly is only active when the pathway is active. Renilla and Firefly have different substrates that give off different wavelengths.
|
|
How does fluorescence polarization work?
|
The ligand is tagged with a fluorscent molecule, and the bound complexes rotate slower and the light isn't depolarized as much.
|
|
What is FRET?
|
Fluorescence Resonance Energy Transfer. The donor/acceptor both emit light, but they're bound, they emit a different wavelength. The exact distance is really important.
|
|
What is FLIPR?
|
Fluorescence Imaging Plate Reader. Based on Ca++ ions and their binding patterns
|
|
What is a scintillant?
|
A chemical compound that absorbs the radiation and emits it as light energy that can be quanitified.
|
|
What is SAR?
|
Structure Activity Relationships - identify the important regions of the lead compound that are important for biological function and use that to improve the drug
|
|
What is SBDD?
|
Structure Based Drug Design - The three dimensional structure of the compound binding the binding site is known
|
|
What is LBDD?
|
Ligand Based Drug Design - The structure of the binding site is not known.
|
|
What is De Novo Drug Design?
|
Structure of the binding site is known, but the lead compound isn't used as a template
|
|
What are the 2D and 3D pharmacophores?
|
2D - functional groups
3D - spatial orientation |
|
What are classical isosteres?
|
Atoms, ions, or functional groups that have the same number of valence electrons and general the same size.
|
|
What are bioisosteres?
|
Atoms or functional groups that share the same physical/chemical properties and produce generally the same biological function.
|
|
What are some bioisosteres of a carbonyl group?
|
-(O=S=O)-
-(C=NOH)- |
|
What are bioisosteres of a carboxylic acid?
|
-(O=S=O)-NH-R
-(C=N-N=N-NH-) |
|
What are bioisosteres of an amide group?
|
replace O with S
|
|
What are bioisosteres of the hydroxyl group?
|
-CH2OH
-NHSO2R -NH(C=O)R -NH(C=O)NH2 |
|
What are bioisosteres of the catechol group?
|
(Benzene with two -OHs next to each other)
Some two ring thingy with Ns |
|
What are bioisosteres of the thioesther?
|
Ether lol
|
|
What are bioisosteres of benzene?
|
Pyridine C5H5N
Thiophene C4H4S |
|
What are bioisosteres of hydrogen?
|
F, -CH4, -Cl
|
|
What is QSAR?
|
Quantitative Structure Activity Relationships
identify and quantify how properties of a drug correlate to biological activity |
|
log P measures _________.
|
drug's overall hydrophobicity
|
|
What is sigma?
|
Measure of the electron donating or electron withdrawing activity of a subsituent on an aromatic ring
+ withdrawing - donating |
|
What is the Hansch equation?
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An attempt to relate three values into one equation in order to evaluate compounds.
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What is the topliss decision tree?
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Flow diagram based on just sigma and pi
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What is 3D QSAR?
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Considers three dimensional structure of the drug as well as the functional groups
Assumes overall size and shape and electronics for binding |
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What is CoMFA?
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Comparative Molecular Field Analysis, graphical and statistical model correlating biological activity to changes in steric or electronic properties of the molecule. Positioned in a grid.
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What are esters used as a prodrug for?
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Carboxylic acids
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What is the rule of three?
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For lead compounds, the MW should be under 350g/mol and the logP should be less than 3
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