Drug Design (I) Flashcards
What are two reactions that render peptides as drugs chemically unstable?
Hydrolysis/oxidation
Why are peptides as drugs physically instable?
Solubility issues
Too big to be orally available, need to be injected via IV
Why are peptides used as drugs despite their weaknesses?
Their strengths are worth it
Good efficacy, safety/tolerability High selectivity/potency Predictable metabolism Shorter time to market Lower attrition rates
How are peptide drugs discovered?
Traditional structure-based design
Ala scan for essential AAs, substitution of labile AAs, Structure-Activity Relation (SARs) EC50, etc
What are 4 common peptide modifications?
AA shortening (smaller = better)
Cyclization (more stable, prevention from exopeptidase and endopeptidase)
Unnatural AAs (D conformation, Beta AAs, N-methylated AA, isosteres)
Glycosylation, PEGylation, etc (standard peptide mods
What are 2 examples of peptidomimetics seen in class?
Consolidation of Beta turns so they’re less floppy (mimicked by cyclic peptides/unnatural AAs)
Stapled peptides (Alpha helices with extra linker to keep helices stable on their own)
What is a property of cyclic peptides, notably bicyclics?
Very stable (if it interacts with its target, it will be very potent)
What was found out about most venomous peptides in nature?
They are cyclic (Cys creates cyclic bonds)
What is a less common feature of carbohydrates discussed in class in the context of Irritable bowel disease?
Glycosylation is one the most common protein modifications
First things you see as you a cell are carbohydrates
What are common properties of carbohydrate drugs?
Lots of hydroxyls and sulphates
Charged, very polar
What is an issue of carbohydrate drugs and why does that not matter?
Too polar to cross membranes, but usually the target is the blood so they don’t need to
How are mannosides useful against UTIs?
Special strand of E.Coli expresses FimH which binds to the mannose residues presented on bladder cells
Mannosides have higher affinity to FimH, disrupt links
How does EB8018 treat IBD?
By disrupting FimH on regular bacteria that trigger an immune response
How does Zanamivir act as a potent neuraminidase inhibitor?
Mimic of transition state, disrupts equilibrium
Modified hydroxyl group (increases affinity 10k x)
Why are Bioisosteres useful?
Can change properties of drug without changing affinity
Or to get around patents
What was the problem with inorganic pyrophosphate as a drug against osteoporosis, and how was it modified to be more effective?
P-O-P link cleaved easily, very short half-life
Modified P-RCR-P (generic bisphosphonate) depending on R groups half life rose drastically
How do organic bisphosphonates work? Is oral administration viable? Why?
Inhibition of FPPS, in turn inactivates Osteoclasts thus preventing bone breakdown
Can be used orally because it’s extremely potent (a minute amount can still have a therapeutic effect)
How does Fluorine act as a bioisostere?
(F & H have roughly the same size but completely different electric properties)
F tends to pull electrons towards it, F-C bonds tend to be VERY hard to break (prolongs metabolism)
A F atom in a certain position can fix a small molecule in a potentially more useful conformation
Can also scan for F in PET
How was Fluorination used to treat the Fentanyl crisis?
Fluorinated fentanyl is nontoxic, shifted pKa to be only effective in inflamed tissues
Same analgesic effects with fewer side effects typically seen in opioids
There is virtually no difference between H and D, why is it used as a bioisostere? (in a way that is not patent circumvention)
C-D bonds are slightly more stable than C-H
If the metabolism of a drug requires the breakdown of C-H bonds, swapping them for C-D can limit that rate
What bioisostere of an amide can you use to make a soft drug?
esterization
