pharmacodynamics - covalent drugs Flashcards
(26 cards)
TCI definition
targeted covalent inhibitors - these drugs incorporate a mildly reactive functional group which forms a covalent bond with protein targets
what are the 2 types of TCIs?
reversible and irreversible
outline the mechanism of action for a reversible TCI
target meets inhibitor, which first interacts via non covalent forces (IMFs, etc) then via a reversible mechanism a covalent bond is formed between the target and the drug
outline the mechanism of action for an irreversible TCI
target meets inhibitor, which firsts interacts via non covalent forces (IMFs) then via an irreversible mechanism a covalent bond is formed between the target and the drug
why is specificity more important for an irreversible TCI?
a non specific irreversible TCI is not good - this means the drug is too reactive, and it probably reacts with many other substances + receptors, possibly also irreversibly, this can cause many side effects - the TCI must be MILDLY reactive
give 4 important qualities for a successful TCI
- good non-covalent/reversible binding to a desired target
- fast + selective reaction with target
- fairly slow/poorly reactive covalent motif, so it only covalently binds with its target
- slowish metabolism allowing drug to reach target (common for all drugs)
give a simplified structure for a TCI
general drug structure bonded directly to a warhead
- general drug structure is what interacts with binding site via IMFs
- reversibly bound to warhead
- warhead is mildly reactive, designed to covalently bond with the target - this group may not be in the active site, could be on the outside so warhead will align with it when drug binds to target via IMFs
give 11 functional groups that can be used as warheads
- acrylamide
- acrylate ester
- propioate
- enone/acrylonitrile
- maleimide
- ester
- acrylonitrile
- α-bromo ketone
- fluoride
- epoxide
- thiol
what are acrylamides/acrylate esters + how do they act as warheads?
acrylamide: -NH-C(=O)-C=C
acrylate ester: -O-C(=O)-C=C
their carbonyl carbons and terminal alkene carbons are both delta +ve, making them good electrophilic sites where nucleophiles can attack via conjugate addition/micheal addition
what are propioates + how do they act as warheads?
-O-C(=O)-C≡C
carbonyl carbon and terminal alkyne carbon are both delta +ve, making them good electrophilic sites where nucleophiles can attack via conjugate addition/micheal addition
what are enones/acrylonitriles + how do they act as warheads?
-C=C(-CN)-C(=O)-R
contains many electron definition carbons which are delta +ve, making them good electrophilic sites where nucleophiles can attack via conjugate addition/micheal addition
what are maleimides + how do they act as warheads?
cyclic diacrylamides that share the same C=C, joined at the N
they have similar electrophilic sites and react similarly
how do esters act as warheads?
carbonyl carbon is delta +ve, this is the only electrophilic site as there is no β-carbon alkene (obviously unless its an acrylate ester)
what are acrylonitriles + how do they act as warheads?
-C=C-C≡N
first alkene carbon is very delta +ve, good electrophilic site for micheal addition
what are α-bromo ketones + how do they act as warheads?
-C(=O)-C-Br
electrophilic carbonyl carbon + Br which is a good leaving group, these groups are good at Sn2 due to carbonyl adjacent to LG
what are fluorides + how do they act as warheads?
just any molecule with an F attached - this is a bad leaving group on most molecules except aromatics, it is a good leaving group for SnAr
what are epoxides + how do they act as warheads?
3-membered heterocyclic ring with one O atom - very reactive electrophile due to ring strain
what are thiols + how do they act as warheads?
anything with an -SH attached - S lone pair is further from the nucleus therefore more available as a nucleophile, it can become an electrophile if oxidised to form -SOH
if a drug has multiple electrophilic delta +ve sites, which is more likely to be reacted with in the body?
most common example of a group with multiple electrophilic sites are groups that have alkenes adjacent to carbonyls/nitriles - here, both the multibonded carbonyl carbon and the further alkene β-carbon are both possible electrophilic sites - the first is a hard electrophile and the second a soft electrophile
most nucleophiles in the body are soft nucleophiles, so are more likely to attack the soft electrophilic β-carbon site to form a new covalent bond
in what field are TCIs most common? (or very common at least)
oncology
what does it mean if a drug ends in ‘-mib’ + give a common subgroup
‘-mib’ = small molecule inhibitor for treating cancer
specifically ‘-zomib’ drugs inhibit protease/proteosomes, enzymes which break down proteins
what does it mean if a drug ends in ‘ib’?
this means it is an inhibitor
what does it mean if a drug ends in ‘-nib’ + give a common subgroup
‘-nib’ = small molecule kinase inhibitors for treating cancer
specifically ‘-tinib’ drugs inhibit tyrosine kinase, an enzyme which phosphorylates particular groups
what type of electrophiles are most warheads?
micheal acceptors
