Part 1 Flashcards
Therapeutic Index
relative safety of a drug; wider = better
Poison
a substance capable of causing an organism harm or death
Drug
a compound that interacts with a biological system and causes a biological response
Drug Target
the macromolecule that a drug binds to
Binding site
usually in a hollow or canyon on the macromolecular target
Binding regions
functional groups on the macromolecular target’s binding site that the binding groups on the drug interact with
Binding groups
functional groups on the drug that interact with the binding regions on the macromolecular target’s binding site
HBA
the group with the electron-rich heteroatom
HBD
the group with the electron-deficient H
Pharmacodynamics
what does the drug do to the body; target interaction
Pharmacokinetics
what the body does to the drug; ADME
ADME
how the drug is absorbed, distributed, metabolized, excreted
Toxin
poison from a biological source
Medicinal Chemistry
study, development, and synthesis of new drugs
What influences how tightly a drug binds?
number and type of intermolecular bonds
Pharmacology
studies how drugs interact with biological targets to produce effects on living systems.
ionic/electrostatic bonds
bonding between groups with opposite charges; strongest of non covalent bonds
hydrogen bonds
- bonding between an electron deficient H and an electron rich heteroatom
- strength of the H-bond is determined by distance, polarity, and bond angle
Van der Waals
-interactions between hydrophobic regions
-requires really close interactions, relatively weak
-induced dipoles
-aka London forces
Dipole-dipole, ion-dipole
- permanent dipole moment leads to partial charges, asymmetrical electron sharing
- strength is between Van der Waals and Ionic interactions
Desolvation
desolvation of binding site and drug are key to drug binding
Primary Protein Structure
- (AKA polypeptide sequence)
- the amino acid polymer chain (a boring shoestring)
Secondary Protein structure
- higher order structures formed by backbone interactions
- alpha helices
- beta sheets
Tertiary Protein Structure:
-folded, three-dimensional structure formed from backbone and side chain interactions
- a lot of diverse IMF’s: ionic/electrostatic, polar, hydrogen bonding, hydrophobic forces, covalent bonding
- the shoe string is a complex woven shape
Quaternary protein structure:
refers to proteins with multiple chains
- 2+ shoestrings fold then group up
What are the hydrophobic amino acids?
ala, val, leu, Ile, pro, phe, gly, met, trp
What are the polar amino acids?
ser, thr, tyr, cys, asp, gln
What are the basic/charged amino acids?
lys, arg, his
What are the acidic/charged amino acids?
glu, asp
What are the names of the beginning and the end of the amino acid sequence of a protein?
first: amino terminus/ N-terminus
last: carboxyl terminus/ c-terminus
Subunit
in proteins with multiple chains, one folded chain is often called a subunit
- Example: the tetramer of hemoglobin has four individual subunits
Domain
domains often refer to an independently folded region of the protein that often have a specific function
- Example: the calmodulin-binding domain
Motif
a small, frequently found protein structure
Example: Zinc-finger motif
Disordered/ Intrinsically Disordered
a section of protein that exists in a disordered, highly-flexible state
What are the types of post-translational modification?
-Acetylation
-hydroxylation
-carboxylation
- phosphorylation
-glycosylation
Amino Acid
the basic unit of proteins
Polypeptide Chain
the amino acid polymer chain
What are the common protein functions?
- structural, transport, enzymes, receptors
Enzymes
a specific type of protein; catalyzes a chemical reaction
What’s a catalyst?
it makes the reaction easier, faster, and lowers the activation energy
- does not change the free energy/ equilibrium
- it does change the rate of the reaction
cofactors
- helper molecules used by enzymes
- additional chemistries available by recruiting a organic molecule or ion
- ex: NADH, PLP, Biotin, FAD
Active site on an Enzyme
a location on the protein that is responsible for binding and catalyzing the reaction
- often a small part of the overall enzyme structure
- active sites can be targets for drugs
- is often more hydrophobic than surface of protein
Active site Amino Acids
- amino acids in the active site are conserved and essential for substrate binding, cofactor binding, and/or catalysis
Strategies for Enzyme-Catalyzed Reactions
- Metal Assisted
- Acid Base
- Covalent Modification
- Approximation and Orientation
- Cofactors are often found in the active site
Covalent Modification
The enzyme may be temporarily (must reset our enzyme) covalently bound to a substrate
Approximation and Orientation
a bond/group is positioned ideally for reaction
Effect of enzymes on reaction rate?
- enzymes can not only speed up the rate but can be a fine tuned way to control/vary the reaction rate
How are enzymes regulated?
- Allosteric effectors
- Post-translational Modification: modifications like phosphorylation can activate or inhibit activity
Isozymes
enzymes with the same function but different amino acid sequence
- often have tissue/cell specific expression
Activation of Ion Channel Receptor
- ion channel is opened when a messenger ligand binds to the receptor binding site.
-Gate opens and ions flow down concentration and potential gradient
Ion channel subunits
- pentameric channel
- may contain different types of subunits or multiple of the same
- location of the ligand binding site varies from one receptor to the next
- each subunit contains 4 transmembrane (TM) regions / helices
What determines ion gate channel size?
channel size is specific for the size and charge of the ion that is going through
What do GPCRs do?
-respond to hormones and neurotransmitters
-embedded in the membrane and activation of GPCR’s leads to activation of G-proteins within the cell
What does GPCR stand for?
G-Protein-coupled Receptors
How fast are GPCR’s?
slower than ion channels bc the have more complex downstream effects
GPCR structure
-All GPCR have a similar structure but vary in sequence, ligand binding, and G-protein binding
-consist of single chain, 7 transmembrane regions, extracellular loops, and intracellular loops
What is the purpose of GPCR extracellular loops?
ligan binding
What is the purpose of GPCR intracellular loops?
G-protein binding
Kinase-linked receptors or Receptor Tyrosine Kinases (RTKs)
- includes and extracellular ligand binding and an intracellular enzyme domain (kinase)
What does a kinase do?
adds a phosphate
Structure of RTKs
- single chains, on transmembrane region
- N-terminus ligand binding
- C-terminus kinase domain
- RTKs can dimerize when a ligand is present
Intracellular receptors
- no embedded in the cell membrane
- often called hormone or steroid receptors
- hormone receptors act directly as transcription factors
- c-terminal ligand binding and a DNA binding domain
Receptor
- Proteins that receive a signal and communicate to the cell
- primary targets for drugs
Messenger Chemical
- aka receptor ligands
- comes in many forms
- simple molecules like amino acids or calcium ions
- complex molecules like peptides or lipids
Ligand
- a molecule that binds to (usually larger) molecules
- similar to a substrate binding an enzyme but causes no catalysis
Neurotransmitter
signaling molecule secreted by a neuron to affect another cell across a synapse
Signal Transduction
the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events
Ion Channel Receptors
- five subunits form a hydrophilic tunnel through the membrane
- closed at rest
Transmembrane Region
- made up of alpha helices
- each subunit contains 4 TM regions
Gating
TM’s have bent structure that closes gate. When opened, bent part sticks out and opens gate. Channels size is specific for size and charge of ions
Zinc Finger Domains
- DNA binding region
- DNA back bone is negative so it binds to positive zinc finger
Substrate
bonds with an enzyme active site
Michaelis Constant
combination of the individual rate constants (k1, k2, k3)/ [substrate] at 1/2 Vmax
Lineweaver-Burk Plots
double-reciprocal plots 1/[s] and 1/Vo
General Features of Receptor Proteins
- mediate cell to cell communication
- frequently located at/embedded in a cell membrane
- receive messenger molecules from CNS and endocrine organs
- to regulate everything
Allosteric Effectors
small molecules that bind to the enzyme at a location away from the active site, activate or inhibit activity
Would you anticipate electrostatic/ionic bonding to be stronger or weaker in the active site of an enzyme?
More hydrophobic. The active site of an enzyme is often partially buried (hollow/cleft), is more hydrophobic than surface and has less water around it resulting in stronger electrostatic interactions due to less or no competition with water
Km constant
can generally tell us how well the enzyme interacts with substrate
- Large Km=weaker substrate interaction
If an enzyme active site contains a conserved histidine residue and it is mutated/changed to an alanine, what issues could arise due to this mutation?
- going from a basic charged aa to a small hydrophobic aa
- could disrupt important intermolecular interactions between histidine and other amino acids or substrate
- likely would impair/kill enzyme activity
alpha helices
helixes held together by local hydrogen bonding between amino acids
beta sheets
strands of the polypeptide chain woven into a sheet, running either parallel or anti-parallel
