Exam 1 Flashcards
What is a drug
An exogenous substance which has a physiological effect when introduced into the body
What is pharmacology
The branch of medicine concerned with the uses,
effects, and modes of action of drugs
What is pharmacokinetics
The study of how drug concentration varies with time
after administration, and how long and where it persists
in the body over time.
Pharmacokinetic parameters are affected by what four processes
Absorption
Distribution
Metabolism
Excretion
What is pharmacodynamics
The study of the relationship between drug concentration
in the body and the response of the body to that
concentration of drug
Fundamental unit of life
Cell
What is the most common type of drug target
Receptors
What is the importance of a cellular response
Affects the physiology and health of the individual
Four major types of receptors
Ligand gated ion channels
G protein receptors
Receptor tyrosine kinases
Nuclear receptors
What non-receptor macromolecules can also be drug targets
Nucleic acids Structural proteins Enzymes Ion channels Cytokines
Drugs are categorized into families based on what three things
- Structural characteristics of ligand or target
- Signaling pathways affected by ligand engagement
- Level of organization targeted by the drug (ex. molecule, organelle, cell, tissue)
What is a structure activity relationship (SAR)
the relationship
between the chemical or 3D structure of a molecule and
its biological activity.
How would you change the “structure” of a drug to alter
its interaction with a target?
Modification of covalent bonds and atomic composition
of a drug can alter its ability to participate in non-covalent
interactions with its target.
What are the four important non-covalent interactions between drug and target
– Number of H-bond donors or acceptors
– Number and type of charge
– Hydrophobicity
– Polar bonds
What are some different types of “activities” that are
affected by the chemical structure of a drug?
-Target potency
-Target selectivity
-Modifications to reduce toxicity
-Scaffold hopping to allow patentability
-Physical properties and formulation
-Modifications for bioavailability
Modifications to modulate metabolism
-Receptor drug interactions
Define principle
a fundamental truth or proposition that serves as
the foundation for a system of belief or behavior or for a chain
of reasoning
What is the central dogma?
DNA –transcription–> RNA –translation–> Protein
What are the three building blocks of DNA
Sugar: Deoxyribose
Phosphate
Bases (Adenine, Guanine, Thymine, Cytosine)
What is the structural difference between deoxyribose and ribose sugar
Deoxyribose: 2’ carbon has H
Ribose: 2’ carbon has OH
Which nucleotide bases are purines
Adenine and guanine
Which nucleotide bases are pyrimidines
Thymine and cytosine
What is a nucleobase
a nitrogenous heterocycle
What is the importance of nucleobases
The endocyclic nitrogens
are basic and can function
as hydrogen bond
acceptors
What is the difference between nucleosides and nucleotides
Nucleosides only contain sugar and base, they lack phosphate
Nucleotides exist in what state
In equilibrium between various phosphorylated forms
What enzymes add phosphate groups
Kinases
What enzymes remove phosphate groups
Phosphatases
Why are di- and triphosphate analogs involved in energy, metabolism, and cell signaling?
Phosphoanhydride bonds are very high energy and cyclization makes them key second messengers
What is the name of the important bonds in single stranded DNA
phosphodiester bonds
Single stranded DNA runs in which direction
5’–> 3’
What is a polymer of nucleotides
DNA
What causes the antiparallel nature of each DNA strand?
Directionality of phosphodiester linkages
What forms between nucleotide base pairs
Dimers (H-bonding)
What happens if drug binding disrupts H bonding in DNA structure
Alters replication and transcription
What phase of the cell cycle is characterized by pre-DNA synthesis?
G1
What phases of the cell cycle are encompassed under “Interphase”
G1 + S + G2
What part of the cell cycle does DNA synthesis occur?
S
What part of the cell cycle does post-DNA synthesis occur?
G2
List the cell cycle phases from longest lasting to shortest
G1>S>G2>M
What is the importance of major and minor grooves in DNA
Allow for interactions with proteins such as transcription factors
Describe the helix-turn-helix motif
- Found in transcription factors
- 1st helix stabilizes interaction with DNA
- 2nd helix often called “recognition helix” because it interacts with base pairs in the major groove
Describe the zinc finger motif
- Found in transcription factors
- Arg 46 and His 49 form sequence (specific contacts)
- 3 nonspecific contacts between PO4 groups and side chains
What are the three steps of transcription
Initiation
Elongation
Termination
What is mRNA
single stranded messenger RNA that serves as the template for protein biosynthesis
True or false: mRNA has secondary structure
True
What is tRNA
Transfer RNA transfers amino acids during protein synthesis. Matches anticodon to codon on mRNA
tRNA forms what type of bond with amino acids?
Ester bond
What are ribosomes composed of
rRNA and protein
What is the site of protein synthesis
Ribosome
What are the two ribosomal subunits found in prokaryotes
30S/50S
What are the two ribosomal subunits found in eukaryotes
40S/60S
Do eukaryotes or prokaryotes have a larger ribosome
Eukaryotes
What are two examples of cancer drugs that form a covalent bond with DNA
nitrogen mustards (melphalan) Platinum complexes (cisplatin)
Melphalan and Cisplatin are alkylating agents that typically attack what specific nitrogenous base (at what site too)
N7 of guanine that is exposed in the major groove
Why is alkylation important in cancer drugs
Alkylation adds on alkyl adducts to DNA, which prevent replication and leads to cell cycle arrest or cell death. Interrupts normal functions of enzymes involved in DNA replication
What non-covalent forces contribute to DNA-drug binding
Van der Waals
H bonding
Electrostatic/ionic
Hydration/dehydration of binding site
Intercalators like doxorubicin use what non-covalent force to intercalate between base pairs?
Van der Waals
Minor groove binders like distamycin use what non-covalent force to bind adenine and thymine rich regions?
H bonding and hydrophobic interactions
What dual binding molecule intercalates and binds to minor groove to cleave one or both DNA strands?
Dynemicin A
What are nucleic acid analogs
Substrates or inhibitors of various enzymes that metabolize normal nucleic acids
What must be done to nucleoside analogs to affect DNA and RNA synthesis
Converted to active forms as triphosphates
Chemical modifications can be made to functional groups at various parts of the nucleotide, what can be done to the base?
Halogenation
Chemical modifications can be made to functional groups at various parts of the nucleotide, what can be done to the sugar?
Hydroxylation/dehydroxylation
Chemical modifications can be made to functional groups at various parts of the nucleotide, what can be done to the phosphate?
Protection by polar groups
Retroviruses need to replicate their RNA. What enzyme do they use?
Reverse transcriptase
What does the enzyme reverse transcriptase do?
Makes DNA from an RNA template
Can reverse transcriptase be found in normal human cells?
No
Zidovudine is an antiviral that acts as a reverse transcriptase inhibitor. How does this medication work?
Its sugar has been dehydroxylated and in place of the OH group on 3’ end it has an azido group. The azido group prevents DNA chain elongation. HOWEVER it can be phosphorylated on 5’ end for bioactivation
Adefovir is an antiviral that acts as a reverse transcriptase inhibitor. How does this medication work?
The sugar ring is opened/eliminated, preventing DNA elongation during replication. The phosphate has been replaced with a phosphonate,
increasing stability
Remdesivir is an antiviral. What characteristics help it to prevent DNA replication?
It is a prodrug with a 1’ cyano group and altered base
How do anticancer agents work and why?
Cancer cells divide rapidly which required DNA synthesis. by blocking DNA synthesis, S phase of cell cycle is stopped.
At what phase of the cell cycle do organelles and cytosolic components duplicate and centrosomes begin to replicate?
G1
At what phase of cell cycle is DNA replicated?
S
At what phase of cell cycle is cell growth continuing, enzymes and proteins are synthesized and centrosome replication is completed?
G2
Fluorouracil is an anticancer agent. What characteristics help it treat cancers?
It is a pyrimidine analog. It is basically uracil that has undergone halogenation (addition of a fluorine)
Fluorouracil (5-FU) can be converted into FdUMP, FdUTP, and FUTP. What does having multiple mechanisms of action do for this molecule?
It allows it to inhibit thmidylate synthase, causes DNA damage, and causes RNA damage respectively.
Cytarabine is an anticancer agent. What characteristics help it to treat cancers?
It is a dehydroxylated isomer of cytidine. It causes DNA damage
Gemcitabine is an anticancer agent. What characteristics help it to treat cancers?
It is an analog of cytidine formed by halogenation. Causes DNA damage
What is a catalyst
A substance that increases the rate of a
chemical reaction, without itself being changed during
the reaction
What is an enzyme
a protein that acts as a biological catalyst
Describe lock and key model
The enzyme and substrate
fit together
Describe conformation selection model
The conformation of the
enzyme varies, one
conformation recognizes
the substrate (ligand)
Describe induced fit model
Binding the substrate
induces a change in the
enzyme
Role of oxidoreductases
Catalyze oxidation/reduction
reactions; transfer of H and O atoms or electrons from one substance to another
Role of transferases
Transfer of a functional group from one substance to another
Role of hydrolases
Formation of two products from a
substrate by hydrolysis
Role of lyases
Non-hydrolytic addition or removal of
groups from substrates
Role of isomerases
Intramolecule rearrangement ie. isomerization
Role of ligases
Join together two molecules
DNA polymerases requires what cofactor?
Magnesium ions
