6. Drug Design Flashcards
What are the 6 strengths and 6 weaknesses of peptides as drugs?
Strengths
- Good efficacy, safety, tolerability
- High selectivity and potency
- Predictable metabolism
- Shorter time to market
- Lower attrition rates
- Standard synthetic protocols
Weaknesses
- Chemically and physically unstable
- Prone to hydrolysis and oxidation
- Tendency for aggregation
- Short half-life and fast elimination
- Usually not orally available
- low membrane permeability
Let’s say you have to proteins A and B. You want to make a drug from A. How do you do this?
The same traditional structure-based design strategies
Take a segment of B and find the AAs that A binds to (the essential AAs)
This is done via an ala scan - turning varying combinations of AAs into Ala to see how binding is affected
Once the essential AAs have been determined, modifications can be made to see how properties are altered
What is the biggest problem with peptide drugs and what are 4 strategies to overcome this?
Short circulating plasma half-life
First line approach is to identify possible enzymatic cleavage sites followed by substitution of relevant AAs. This can also be done with a secondary structure (having the protein fold). This approach includes lactam bridges, stapling or clipping, or cyclization
Other strategies involve binding to albumin to extend the half-life (sometimes to the order of days), which involves peptide acylation, insertion of albumin binding peptide elements in the backbone, or conjugation to albumin binding antibody fragments
PEGylation has also been used to limit globular filtration (thus increasing half life) by limiting the elimination of peptides.
Formulations (an implanted device that delivers peptide therapeutics from a dry resevoir for up to a year) have also been explored
Name the peptidomimetic learned in class, and the peptidomimetic proposed “in the pipeline”
What is a very stable form of peptide found in the clinic, and where can they be found in nature?
Cyclic peptides/unnatural amino acids can mimic beta turns and fix them in place, increasing stability
Later: stapled peptides (several carbon linkers keeping alpha helix in place)
Cyclic peptides are quite stable (if they can interact with their targets they will be very potent) NB Many Cys aas here for stability
Most cyclic peptides in nature are venomous
What are carbohydrate drugs and what are their drawbacks? What is the use case that was learned in class?
Drugs that mimic carbohydrates
Addresses the problem of low activity from carbohydrate leads
Very low passive diffusion (way too polar)
Slow hydrophilic molecules (rapidly passed by kidneys)
Interacts with Lectin weakly, but in great numbers
Useful in UTI and IBD (bacteria forms fibers to bind the cell wall, mannose residues disrupt FimH protein which makes those fibres)
What are bioisosteres? What are the 4 effects that a bioisostere could have on a drug:target interaction?
Drug groups / molecules that ‘look’ the same to the target, but have different properties
- Can change the structure to maintain a preferred conformation
- Receptor interactions (must be very similar in terms of size/shape/electronic properties, etc)
- Pharmacokinetics: usually done during/after optimization of direct biological response. lipophilicity, hydrophilicity, H bonding and pKa become important here
- Metabolism: some moieties block/assist metabolism
What are the effects of swapping a C-H bond for a C-F bond?
Achieves metabolic stability
Reduces basicity of proximal amines
Increases acidity of proximal acids
Introduces a conformational bias in molecules
(might influence membrane permeability)
PET spectroscopy
What is the effect of swapping a C-H bond for a C-D bond?
Basically nothing
C-D is slightly more stable than C-H
If the metabolism of a drug requires the breakdown of a C-H bond, swapping it for a C-D bond limits that rate (must be RLS)
What is the effect of amide/ester isosteres?
esters are broken down easily
Good for a soft drug, bad if not
Describe transition and intermediate states during an enzymatic reaction and explain how transition state analogues are effective
What are the drawbacks of transition state analogues?
Normally:
The enzyme binds a substrate, and a significant energy investment converts the substrate to a transition state. This transition state is extremely transient (last approximately 1 molecular vibration cycle) before settling into an intermediate molecule (a local minima which can last up to days) before requiring another energy investment
A transition-state analogue requires a negative energy investment and are thus binds the analog preferentially, making the investment to the transition state lower.
Transition state analogues typically inhibit the enzyme, making them quite effective
The mechanism has to be well understood to capture the true transition state to make an analog
Important to distinguish between transition state and intermediate
What are 6 ways to conver specificity of a drug to an enzyme and not another enzyme (or ‘decoy’)?
Optimize ligand charges
Target allosteric site
Create clash with decoy*
Remove interactions in decoy*
Bind to distorget target site where decoy is rigid
Displace high enery water not present in decoy
* Ensure structural rearrangement does not allow decoy binding
How can eg cancer/infectious diseases mutate the target protein in a way that allows a resistant mutant to emerge? How can resistance be avoided?
In cancer/infectious diseases, the target protein can mutate such that the protein is still active but interactions with the inhibitor are interfered
Typically due to a mutation in side chains. Drugs that interact with the backbone may be useful
Flexible drugs may also be used: drugs that can adapt to mutations via wiggling (torsional changes) and or jiggling (reorientation/repositioning)
Describe the substrate envelope hypothesis
To achieve broad binding selectivity against an enzyme target and the collection of its functional mutants, a useful approach has been to develop inhibitors that bind within and do not extend beyond the envelope created by the outer shape of the substrate(s)
What are covalent inhibitors? Why are scientists shying away from developing them?
Drugs that bind an enzyme to inhibit it via a covalent bond
Essentially irreversible
Sying away due to risk of strong side effects
What are the two types of covalent inhibitors? How do they differ?
Mechanism-based / suicide inhibitors: directly target a catalytic nucleophile within the active site of the enzyme*
*Problems with specificity (active sites are conserved in eg all proteases)
Targeted covalent inhibitors: target a non-catalytic nucleophile that is poorly conserved across the target protein family**
**Better for selectivity but must be close to active site
What two drivers govern selectivity in covalent inhibitors? What determines the reaction rate when taking safety measures into account?
The initial binding step (KI) and subsequent chemical step (k2)
KI must be high enough to ensure the compound binds selectively and with a residence time sufficient for a covalent reaction
k2 must be high enough to give a high probability that th ereaction will occur within the lifetime of the non-covalent complex
Since highly reactive electrophiles must be avoided, the rate is achieved by the optimal positioning of the electrophile relative to the nucleophile on the target
What does the rainbow diagram seen in class represent?
The -fold increase necessary to ‘justify’ adding different groups to your molecule
Adding small molecules doesn’t affect LE much so they’re relatively low-risk, large (aromatic) molecules would have to make your compound much more effecient for it to be worth adding
(The same diagram can be made for lipophilicity instead of size)
Graph does not always look like this, could add something far to the right and not increase LE by that much, meaning it was not worth adding (or vice versa)
