final review of earlier modules Flashcards
describe competitive inhibitors
compete with substrate for same active site
alter km and kcat
describe non competitive inhibitors
bind to diff location prevent ES formation
alter k cat and vmax
describe uncompetitive inhibitors
binds to ES, alters ES structure prevents catalysis
alters Km, Kcat, Vmax
what is Km
concentration of substrate at 1/2 vmax, enzyme efficiency
what is Vmax
maximum velocity of the reaction
what is Kcat
turnover rate, how efficiently ES into products
what is Kd
binding between E + S
what is an irreversible inhibitor
- binds covalently, alters conformation or disables function group
- penicillin
2 methods of receptor signalling
1) binding of messenger changes conformation allowing another molecule to bind or be released
2) binding of messenger changes conformation of receptor allowing or destroying catalytic function
what is an agonist
- binds to active site in the same place messenger would
- induces shape change which sends out a signal
what is a partial agonist
1) non ideal conformational change, leads to a weaker signal produced than agonist and lasts for certain duration
2) binds in more than one way (agonist + antagonist)
what is an antagonist
- Drug binds to receptor in such a way that an abnormal shape change is produced. This results in no signal transmitted. The drug prevents the messenger from binding, preventing signal from being produced.
what is an allosteric agonist
- binds to different location on receptor
- alters active site making it easier for messenger to bind
what is an inverse antagonist
- reversal in receptor function
- only if receptor has background activate (signal in absence of messenger
- antagonist shuts off background signal
- apparent reversal
phase 1 clinical trial
- max safety dose
- 100 patients
- VOLUNTEERS
- less than 1 year
- 30% fail
phase 2 clinical trial
- safety, efficacy
- max effective dose
- 200-300 patients
- less than 1 year
- 70% fail
phase 3 clinical trial
- safety, efficacy
- monitor rare side effects
- thousands of patients
- less than 1 year
- 70% fail
4 types of excipients
- non medicinal ingredients, usually from food industry
- stabilizers: acid/base protect from degradation due to oxygen
- preservatives : prevent bacteria or mold
- disintegrates: help deliver drug, starch
- flavours: sweetness for kids, safety in adult medication
- colours: safety and identification
- fillers: ensure correct dosing, cellulose, MgSO4
4 types of formulation
-pills, capsules, liquids
- digested orally
topical cream, patch, nasal spray, eyedrops
- bypass liver, if ingested may not reach bloodstream fast enough
4 requirements for animal testing
2 species
1 must be primate
show that drug is bioavailable (gets in body)
must use relevant dose
solvent exposed binding pockets
see doc
how does bacteria overcome b-lactam
- b lactamase
- opens b lactam ring, drug can no longer inhibit peptidase
how to overcome bacterial resistance
- add larger group to side chain of penicillin
- no longer fits into b lactamase, can’t be deactivated
- fits into transpeptidase and inhibits it
what is a classical isostere
- same valency + similar size
- helps determine if groups important for binding or not
what is a non classical isostere
- similar bio or chem properties
- differ in steric and electronics
what was the first commercially successful drug and how did it work
- sulfanilamide
- competitive inhibitor (competes with PABA for active site)
- inhibits bacteria enzyme from forming co enzymes F needed for growth
3 amino acids in catalytic triad and functions
- aspartic acid
- histidine
- serine
role of oxyanion hole
stabilize -ve oxygen in tetrahedral intermediate
lipinski rule of 5
if 2 or more: not bioavailable
SHOULD NOT HAVE
- more than 5 h bond donors
- more than 10 h bond acceptors
- molecular weight > 500
- C/ log p > 5, MlogP > 4.15
- Log D 1 < x< 3
