Module #2 - Biotargets of Drugs Flashcards
4 main types of biological moleules
proteins, nucleic acids, polysaccharides, and lipids
proteins
linear chain of amino acids connected by amide (peptide) bonds
nucleic acids
linear chain of nucleotides connected by phosphate esters
polysaccharides
linear chain of sugars connected by acetals
lipids
linear chains of acetate or propionate connected by reduced aldol
importance of modular characteristic of biological molecules
allow for complex structures to easily be assembled and disassembled
what “machine” puts together proteins
ribosomes
what “machine” takes apart proteins
proteasomes
what is the typical process of drugs in the body
drug attaches to biological target of a biological molecule (usually a protein) –> results in a biological change (usually a change in shape on protein) –> results in a biological response (ex. lower blood pressure)
importance of 3d properties of biomolecules
allows for biomolecules to bind and be recognized
how many amino acids
20
general composition of an amino acid
amine, acid group, and carbon side chain of some sort
what is the stereochemistry of the side chain of an amino acid
always at the back
primary structure of proteins
a linear chain of amino acids
listed in order from N-terminus to C-terminus
what is the n-terminus of an amino acid
the amine portion
what is the c-terminus of an amino acid
the acid portion
what connects for proteins to form
the n terminus (amine portion) connects to the c terminus (the acid) of another amino acid
secondary structure of proteins
the regular, local structure of the protein backbone
a-helix, beta sheet, loop, turn
why do secondary structures form
due to restrictions in protein chains specifically:
- conformational restrictions in amide bonds
what are two main characteristics of amide bond:
sp2 hybridization due to blend of resonance forms, so the structure is flat
can either get a sigma trans or a sigma cis conformations
what happens if you get a sigma-trans conformation of an amide bond
large groups are away from each other and don’t interact
amide bonds will always choose this option if possible because more stable
what happens if you get a sigma-cis conformation of an amide bond
large groups are close to each other and interact
characteristics of side groups of amide bonds
can be +, -, or nothing (only H)
negative charges attract positive charges
H bonding occurs between size chains and backbones
non-polar size chains interact with other non-polar chains
what is a localized structure
the sum of all the effects of side chain interactions on a protein chain adding together
characteristics of alpha helix structure
spiral shape
represented by ribbon diagrams
characteristics of beta strand
everything is in same plane
flat in nature
side chains stick out
characteristics of beta sheet
formed by several beta strand associating together
can be parallel or antiparallel
held together by hydrogen bonds
parallel beta sheet
both sheet go in same direction (n-c, n-c, etc.)
antiparallel beta sheet
sheets go in opposite directions (n-c, c-n, etc)
characteristics of beta barrel
large beta sheets curling around themselves to form a cylinder
characteristics of loops
area with no defined secondary structure
looks like spaghetti
tertiary structure of proteins
combination of all secondary structures added together
result of interactions between non-adjacent regions
tertiary structure of proteins
combination of all secondary structures added together
result of interactions between non-adjacent regions
what do secondary structures result from?
side chains interacting with each other (adjacent regions interacting)
what type of bonding exists in tertiary structures
lots of noncovalent
what are the four attractive forces in tertiary structures (strongest to weakest
disulphide
ionic bonding
hydrogen bonding
van der waal
disulphide bonding
strongest covalent bond
involves formation of disulphide bond
ionic bonding
involves a complete positive and complete negative charge being attracted to each other
hydrogen bonding
involves hydrogen being attracted to a pair of electrons on an atom
van der waal
involves greasy side chains interacting with greasy side chains (non-polar + non-polar interactions)
why are van Der Waals so important
because allow for inside of protein to be non-polar and outside to be polar which allows for a strong structure
polar + polar
weakened bonds
polar + nonpolar
strengthened bonds
quaternary structures
combination of two+ tertiary structures binding together
two ways that quaternary structures can form
either proteins can be the same or different
what type of interactions occur in quarternary structures
protein protein interactions
why are protein protein interactions so strong
lots of surface contact area
lots of chemical interactions
exclusion of water from space between
proteins stick together tightly
how are quaternary structures formed
proteins have big surface areas which allows them to come together easily and have a strong interaction
water squeezes out from in between, and the proteins stick together
is most of a protein functional?
no, most if scaffold - only very small part is the active site
what are the four types of protein targets for drugs
enzymes
receptors
ion channel
structural proteins
how does a drug work if it has an enzyme as target
it functions to stop the enzyme from working
most drugs are enzyme inhibitors
how does a drug work if it has a receptor as a target
drug activates (agonist) or deactivates (antagonist) the receptor
some drugs do both
how does a drug work if it has an ion channel as target
drug works to open or close the channel
some drugs do both
how does a drug work if it has a structural protein as target
can interfere with assembly or disassembly of certain protein structures
what is an enzyme
special group of proteins that catalyze reactions
create custom perfect environment for reaction to occur
lowers the energy of transition state so the reaction will go faster
what is the active site of an enzyme
where the chemical reaction takes place
very small
chemical environment characteristics for an effective enzyme
complementarity of chemical properties important (must be positive and negative charges)
typically an acid base mechanism occurring when active site of enzyme touches substrate
general steps of enzyme catalyzed reactions
enzyme binds to substrate forming enzyme substrate complex
enzyme typically changes shape to accommodate substrate + substrate also changes shape and joins active site of enzyme
substrate converted into product in active site of enzyme
equilibrium creates between product and enzyme, and product diffuses away
what are two theories of enzymatic conformational change
lock and key
induced fit
lock and key theory
states that enzyme is the exact shape necessary for substrate to fit into
substrate and enzyme don’t change shape for each other
induced fit theory
states that the binding of a substrate and other molecule with an enzyme changes the shape of that enzyme
conformational change in shape activates or deactivates the enzyme
more realistic than lock and key
what is involves in michaelis-menten kinetics
used to describe enzyme efficiency
states that enzyme and substrate come together to form enzyme substrate complex
shows kinetics behind enzyme catalyzed reactions
what is a Michaelis menton plot
tracks how an enzyme produces product over time
what are the three main types of enzyme inhibition that drugs can perform as
competitive inhibition
noncompetitive inhibition
uncompetitive inhibition
competitive inhibition
drug (inhibitor molecule) competes with substrate for active site
binding occurs within the active site of enzyme
inhibitor binds to active site, eating the substrate cannot bind, and preventing the product from being produced
noncompetitive inhibition
drug (inhibitor molecule) bind to enzyme, but not in the active site, and changes the shape of enzyme
the substrate binds to active site inside
drug is not necessarily competing with substrate - they both bind to respective locations
uncompetitive inhibition
drug (inhibitor molecule) binds to enzyme-substrate complex
binding destroys the catalytic ability of the enzyme substrate complex
substate binds first, changes the shape, and then the drug can attach (to the enzyme/substrate complex)
how do competitive inhibitors change plots
kinetics are changed, max is not
y-intercept stays same, slope does not
example of competitive inhibitor
disulfiram
drug for alcoholics
blocks the chemical that stops your body from getting sick due to hangover
how do non competitive inhibitors change plots
changes both slope and y-intercept
km is unaltered - meaning substrate can still bind to free enzyme
vmax reduced - meaning inhibitor changes the enzyme substrate complex
example of noncompetitive inhibitor
fluconazole
side effect of interfering with enzymes in liver and prevents them from working
what is a fourth type of enzyme inhibition (unofficial)
irreversible inhibitor (covalent/suicide inhibitors)
bond covalently to enzyme, and inhibit by altering conformations/disabling functionalgroups
block function of enzyme by forming a covalent bond between themselves and the enzyme
example of uncompetitive inhibitor
lithium
exact mechanism is unknown
example of irreversible inhibitor
penicillin
what is a receptor
a molecule that moves information from one place to another (usually from inside to outside of cell, or vice versa)
specialized proteins embedded in cell membrane
what changes the shape of a receptor
interactions between messenger and the receptor
how do receptors work?
receptor and messenger come together
shape changes upon interaction
something becomes activated on the other side of membrane that allows information to be carried
once information has been transmitted, the receptor spits out the messenger and starts the process thin
what are the five types of drug classes
agonists, antagonists, partial agonists, inverse agonists, and allosteric agonists
what is an agonist
essentially replaces the messenger
transmits information/amplifys signals without messenger present
creates a shape change that is same/similar to regular messenger
what is an allosteric modulator
works with ion channels
bonds to channel, just not in same location as regular messenger
this changes the shape/sensitivity towards normal messengers –> alters the way the receptor will act with messenger going forward
what is an antagonist
induces abnormal shape change of receptor so that it is not accessible by regular messenger molecule + there is no signal transmission (no transmission of information)
may bind at active site, or other locations (like allosteric sites)
what is an allosteric antagonist
basically binds in some location on receptor molecule, and alters the actual messenger binding site so that the messenger can no longer bind
what is a partial agonist
similar to agonists, but not as strong - are more weak
binds to receptor, and produces a non-ideal conformational change allowing for a weak signal to be sent
can either bind in an agonism way, or in an antagonism way
what is an inverse agonist
essentially seem to give a reverse reaction
drugs are inverse agonists depending on interactions with receptor, not drug itself
wipe out any weak background signals on receptor (instead of amplifying it - like other drug classes do)
what is the biological effect of an agonist
as you increase concentration, biological response increases
ex. blood pressure increases
what is the biological effect of a partial agonist
as you increase concentration, the biological response increases (just not to the same degree as a full agonist)
ex. blood pressure increases, just not as much as a full agonist
what is the biological effect of an antagonist
blocks the action of the receptor + results in no response
prevents signals from being transmitted
concentration doesn’t appear to have an effect on level of biological response - there will always be no activity no matter the dosage
ex. blood pressure remains the same
what is the biological effect of an inverse agonist
reverse reaction occurs
goes in opposite direction
ex. blood pressure decreases
types of biological assays
high throughput screening
routine SAR work
kinetics or special studies
