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Fischer's Lock + Key hypothesis
Enzyme (EZ) + Substrate (S) seen as rigid strucs w/S fitting perfectly into active site
Doesn't explain how EZ catalyse reac. w/diff S
Koshland's Induced Fit Theory
Active site changes shape when S enters w/induced bonding
Acid-base catalysis
Often seen in histidine (AA)
Peptide hydrolysis (w/chymotrypsin- Ser, His, Asp)
Hydrolysis of acyl grp from Ser proceeds well as esters more reactive than amides, hydrolysis of peptide link= loss of half of peptide, room for H2O to enter
Co-factors
extra non-prot substances required by many EZ for reac to take place
most bind by ionic/NC interacs
Covalently bound co-factors are called…?
Prosthetic grps
Mech. for lactic acid + NAD+
Phase I development
20-100 healthy volunteers, small dosage
Phase II development
100-500 patients w/disease
Phase III development
1k-10k patients, test for adverse effects/toxicity
What is SAR?
Struc. Activity relationships= relationship bet chemical struc of molecule + its bio activity
Chloesterol
Fatty, can’t dissolve in blood
Transported around body by low (LDL)+high density lipoproteins (HDL)
Make + remove plaques
Statins
Inhibit co-EZ, competitive, bind more strongly than nat. S due to polar head grps
Difference bet. type I and II statins
Type I- from fungal metabolites (e.g. Pravastatin)
Type II- fully synthetic (e.g. Atorvastatin)
ACE inhibitors
antihypertensive drugs- treat high bp
catalyses dipeptide hydrolysis
binding reversible + competitive
(e.g. Lisinopril or enalaprilate)
Transition state analogues
Drugs that resemble transition state for catalysed reaction
effectively irreversible
should bind stronger than S or P
e.g. renin inhibs
Antihypertensive drug
Inhibits step 1 in synth of angiotensin II
Renin-catalysed hydrolysis mech
renin inhib e.g. Aliskiren
Aliskeren- renin inhib e.g.
has hydroxyethylene moeity- tetrahedral geometry + ½ OH grp for good binding
stable to hydrolysis as no leaving grp present
e.g. of Allosteric inhbitor
6-Mercaptopurine, treats leukemia by inhibiting first EZ involved in purine + DNA synth
How can fungal strains be used to make antibiotics
Many make metabolites that act as bac. EZ inhibs but have no effect on fungal EZ
e.g. Cephalosporin C, sulphonamides
Sulphonamides
MoA: inhibits cell metabolism- blocks the biosynthesis of tetrahydrofolate
treats UTIs, gut infections, eye lotions
e.g. sulphadoxine
Sulphonamides SAR
R2 is only site that can be varied
Pencillins MoA?
Inhibit cell wall synth- irreversible inhibiton of transpeptidase EZ
Stop final cross coupling reaction
e.g. Amoxcillin, Ampicillin
Non-toxic irreversible inhibs (pencillin) by…
Penicillin covalently linked by ester link to Ser residue- irreversible
Steric shield prevents S or H2O access
Pencillin mech
Overcome bac. resistance by using
Suicide substrate
How do bac develop resistance to pencillin?
Make B-lactamase EZ catalyse hydrolysis of B-lactam ring in penicillin
Pencillin hydrolysis w/B-lactamase mech
Clavulanic acid + mech
Taken w/penicillin to stop B-lactamases
e.g. Augmentin
Drug that inhibs DNA polymerase, treats herpes, shingles
Aciclovir
Drug that inhibs HIV protease
Saquinavir, poor bioavailability + drug resistance
Zn-dependent EZ
important role in metastasis of cancer cells
MMP inhibs?
Inhib breakdown of extra-cellular matrix
difficult for cancer cells to metastasize
e.g. of peptide-based inhib?
Marimastat
Strongly interacs w/Zn2+ cofactor
At least one func grp capable of forming H-bond to EZ backbone
AstraZeneca developed anti-cancer agents called…?
4-anilinoquinazolines (prot. kinase inhibs of EGF-R)
How was H2O solubility in getifinib
Morpholine ring
Note 
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