Lecture 5 Part 1 Flashcards
what is the drug competing with to bind to the receptor site?
the natural substrate
as mentioned, a drug has to compete with the natural substrate for the receptor site.
how does the drug compete?
the drug must make a number of specific interactions with the atoms/groups of atoms at the receptor site
as mentioned, in order to compete with the natural substrate, the drug must make a number of “specific interactions” with the atoms or groups of atoms at the receptor site.
what are these “specific interactions”?
chemical bond forces – either covalent or noncovalent
which of the chemical bond forces is considered irreversible/permanent?
covalent bond
do most drug-receptor interactions use covalent or non-covalent forces?
most use non-covalent
the bonds that exist within methane are irreversible
(true or false)
methane = CH4
TRUE. the atoms are held together by covalent bonds
however, if you put a tremendous amount of energy, it can be broken. however, this is irrelevant at physiological conditions
true or false
the forces that hold methanol together are reversible
methanol = CH3OH
FALSE–held by covalent bonds
methane is ____ at room temp while methanol is ___ at room temp
methane = gas
methanol = liquid
the interactions that take place between the drug and the receptor site (when the drug is competing with the natural substrate) use the SAME BONDING FORCES involved with….
when simple molecules interact (covalent and noncovalent bond)
true or false
covalent bonds are the strongest of those involved in drug-receptor interactions and is considered irreversible
true
in most cases, what drug-receptor interactions are desirable?
ionic or weaker bonds (noncovalent— reversible)
when would covalent bonds be desirable in drug-receptor interactions?
if you want relatively long lasting or irreversible effects (provided that you have high specificity)
ex:
anti cancer
anti bacterial
true or false
for sedating and hypnotic drugs, we would want the drug-receptor interaction to be via a noncovalent mechanism
TRUE - we dont want it to be irreversible and we never wake up, but we still need a reasonable duration of action to sleep through the night
name all 7 types of chemical bonds, from strongest to weakest
strongest - covalent
reinforced ionic
ionic
hydrogen, ion-dipole, dipole-dipole
weakest - van-der walls
explain the duration of a reinforced ionic bond
it is NOT permanent.
the drug-receptor interaction will come off in time, but it may be a decent amount of time
explain a reinforced ionic bond
it is an ionic bond (+) (-) interaction that is reinforced with additional forces, such as hydrogen bonds as an example
give an example of when van der waals forces would exist
between hydrocarbons
bond strength is represented in what units?
kcal/mole
name 3 ways in which covalent bonds are used in drug-receptor interaction
alkylation
acylation
phosphorylation
what is an alkyl?
a functional group with ONLY carbon and hydrogen atoms, arranged in a chain
give an example of a nitrogen mustard.
what is it used for?
what is its mechanism?
mechloroethamine – chemotherapy drug
it is an alkylating agent that acts through the formation of COVALENT BONDS
mechlorethamine has a tertiary amine functional group that acts as a nucleophile and attacks the beta carbon which, in turn, “kicks out” the chlorine atom, which is a good leaving group, forming the AZIRIDINIUM ION. (highly electrophilic intermediate)
this aziridinium ion then gets attacked by a nucleophile (purine/pyrimidine DNA bases) which breaks the 3 membered ring and attaches there in place of the chlorine
the same reaction occurs again, kicking out the remaining chlorine atom and again producing aziridinium ion, this time with one side attached to DNA a base
this highly electrophilic ion gets attacked by purine/pyrimidine bases again, and there are now two “R” groups (the DNA bases) on the molecule
this forms an INTERSTRAND CROSSLINK which permanently stabilizes the double strand DNA, preventing dissociation and thus replication of cancer DNA
are there any unintended side effects of using the mustard gases (mechlorethamine)?
YES. DNA is prevented from replicating. Thus, cells that replicate fast such as hair and bone marrow, can be affected by this
in the mechanism of action of mechlorethamine, what is the “driving force” that kicks out the chlorine atom?
the electron pair on the tertiary amine.
carried out by the beta carbon
“3 membered ring with a positive charge”
what is this?
azyridinium ion
besides mechlorethamine, name another alkylating agent, as well as its properties
cyclophosphamide. has the same covalent bond interaction with tumor DNA as mechlorethamine however, cyclophosphamide has a higher therapeutic index, meaning it is safer
the larger the therapeutic index, the ___ the drug
safer
alkylating agents are typically what kind of drugs?
anti cancer (mustard gases)
what kind of drugs perform acylation?
beta lactam antibiotics (penicillins and cephalosporins)
they acylate bacterial cell wall constituents acylate an enzyme required for integrity of the bacterial cell wall. it is the enzyme for peptidoglycan synthesis which cross links bacterial cell wall constituents
what is acylation?
the addition of an acyl group (R-C=O)
true or false
the acylation of bacterial cell wall constituents by beta lactam antibiotics is irreversible
TRUE happens via covalent bond forces
what is a relatively rare feature of the beta lactam antibiotics?
the beta lactam ring – a 4 membered, cyclic amide
explain the mechanism of action of beta lactam antibiotics
a nucleophile attached to the drug receptor (peptidoglycan enzyme) attacks the carbonyl carbon of the beta lactam ring.
this forms a covalent bond between the bacterial enzyme and the beta lactam antibiotic, preventing the enzyme from synthesizing peptidoglycan, a component necessary for the bacterial cell wall of gram positive bacteria. the bacteria cannot survive in these conditions
are beta lactam antibiotics nucleophilic or electrophilic?
electrophilic due to the energy in the 4 membered ring – the partial positive charge on the carbonyl carbon contained in the ring
this is what gets attacked by the nucleophile
what gives the beta lactam antibiotics stability?
the presence of the 5 membered ring fused with the unstable 4 membered beta lactam ring
explain why it is justified to use covalent bond force in the case of beta lactam antibiotics
the drug is HIGHLY SPECIFIC TO THE TARGET. the bacterial enzyme that makes peptidoglycan is not found in humans. therefore, we are able to take a lot of penicillin without it affecting us because our body does not contain the enzymatic target of the beta lactam antibiotics
“4 membered cyclic amide”
beta lactam ring
explain the mechanism of action of organophosphates, and name an organophosphate
organophosphate = malathione
malathione undergoes desulfurization to produce malaoxon. the phosphate on malaoxon gets attacked by a Serine -OH group on acetylcholinesterase, displacing the sulfur, to form a PHOSPHATE ESTER
this produces an IRREVERSIBLE COVALENT BOND on acetylcholinesterase with organophosphate
once acetylcholinesterase is bound, acetylcholine is permanently in the synaptic cleft, producing a constant stimulation of the muscle, leading to paralysis
organophosphates
NOT human drugs. commonly the main component in insectisides.
target is acetylcholinesterase to produce paralysis
are organophosphates safe to use?
the target of organophosphates is very small (an enzyme in insects).
hence, it is safe for humans to use in small amounts, but it must be considered that humans DO have the target enzyme, so exposure should be kept at a minimum
true or false
if there was an effective delivery system, organophosphates could kill people very fast
true
what is the strongest of the 3 covalent mechanisms mentioned?
alkylation is stronger than acylation and phosphorylation, but all 3 are still irreversible
true or false
phosphorylation is reversible
FALSE – IRREVERSIBLE.
uses covalent bonds
name 4 common acidic groups found on drug receptors
glutamate and aspartate (organic)
phosphate and pyrophosphate (inorganic)
not as common as phosphate = sulfate
acidic groups on the drug receptor favor binding to drugs containing ___ groups
BASIC
name 3 basic groups found on drug receptors.
which 2 are more common?
arginine guanidino group
lysine amino group
Histidine imidazole nitrogen (NOT AS COMMON)
which is more basic — guanidine or the amino group on lysine?
amino group on lysine
at physiological pH, what will happen to arginine guanidino group?
will get a proton added (basic)
the histidine imidazole nitrogen is most commonly used in what kind of reaction?
an acid-base transfer
basic groups on the receptor favor binding drugs containing ___ groups
ACIDIC
