Lecture 5 Part 1 Flashcards by amanda kastel

what is the drug competing with to bind to the receptor site?

the natural substrate

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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

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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

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which of the chemical bond forces is considered irreversible/permanent?

covalent bond

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do most drug-receptor interactions use covalent or non-covalent forces?

most use non-covalent

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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

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true or false

the forces that hold methanol together are reversible

methanol = CH3OH

FALSE–held by covalent bonds

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methane is ____ at room temp while methanol is ___ at room temp

methane = gas
methanol = liquid

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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)

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true or false

covalent bonds are the strongest of those involved in drug-receptor interactions and is considered irreversible

true

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in most cases, what drug-receptor interactions are desirable?

ionic or weaker bonds (noncovalent— reversible)

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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

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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

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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

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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

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explain a reinforced ionic bond

it is an ionic bond (+) (-) interaction that is reinforced with additional forces, such as hydrogen bonds as an example

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give an example of when van der waals forces would exist

between hydrocarbons

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bond strength is represented in what units?

kcal/mole

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name 3 ways in which covalent bonds are used in drug-receptor interaction

alkylation
acylation
phosphorylation

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what is an alkyl?

a functional group with ONLY carbon and hydrogen atoms, arranged in a chain

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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