Medicines Design Flashcards
What is the key change in salbutamol, making it selective to B2 receptors?
Replacing the phenol with a Hydroxymethylene group
What are the key SAR points for Beta agonists (from cathecholines)
Phenol groups important for H-bonding
Large N-alkyl groups lead to selectivity for B-adrenoceptors
Protonated N-amine allows for ionic interactions Aromatic ring –> for VDW forces
Give a few examples of where lead compounds (in SAR) can be found?
Why aren’t these compounds used directly as clinical drugs?
Natural receptor ligands (eg, ACh/NA)
Natural products (eg, muscarine)
Collections of synthetic compounds
These would not be used clinically as they would have many side effects
What is the function of Neuraminidase and Hemmaglutinin?
Neuraminidase –> An enzyme that breaks down the sialic acid receptor of the cells surface
Hemmaglutinin –> Compromised of the globular head and fibrous stem. The globular head binds to the sialic acid receptor
What do the following class of drugs act on?
And what do they block?
B2 Agonists
Antimuscarinics
B2 Agonists –> Bind to adrenergic receptors, blocking noradrenaline
Antimuscarinics –> Bind to muscarinic receptors, blocking ACh
Why is prednisolone more active than cortisone?
As it is flatter, so it binds to the receptors with more affinity/potency. Whereas cortisone has sp2/3 groups, so its not flat
What is the influenza vaccine?
A tri-valent inactivated vaccine, created by egg propagation
The bacteria/virus is grown in a culture media, then inactivated using heat/chemicals
Benefits –> Safer and stable
Negatives –> Costly, and can cause hypersensitivities
What was the main problem with ACh as a drug?
And how did SAR end with Ipratropium?
Main problem was that ACh had many rotatable bonds, which allowed a lot of off-target binding
Was found that the ester group was important, as well as a positively charged tertiary nitrogen.
A rigid structure also improved the specificity, for example, aromatic rings
What are the first line and second line drugs for the treatment of TB?
First Line –> Isoniazid (or streptomycin), Rifampicin, Pyrazinamide and Ethambutol
Second Line –> Ciprofloxacin (or another fluroquinolone)
Explain the basis behind Zanamivir (Relenza) and Oseltamivir (Tamiflu) And when are these drugs most important?
Zanamivir –> A guanadino group was used to replace the 4 OH group near the sialic acid. This allowed neuraminidase specificity, and for H-bonds to be formed with glutamate (on neuraminidase)
An inhaler
Oseltamivir –> Modification made to improve BA
Tablets or a syrup
Most important during epidemics, as there is no protection!
Describe the structure of influenza
ssRNA
Enveloped
An orthomyxovirus
Has both Neuraminidase (cleaves sialic acid from glycoconjugates) and Hemmaglutinin (binds to sialic acid receptors)
Explain the 4 types of influenza?
A, B, C and D
A and B are causes seasonal epidemics (over winter)
Type C causes respiratory disease
Type D effect cattle and not humans
Explain what chelates are
Insoluble salts that bind to divalent cations (eg, Ca2+) and cannot pass through biological membranes
So if chelation occurs, the nutrients will not get into the gut
What is the purpose of mineralcorticoids?
They regulate electrolyte balance, espeically salt levels (Na+)
What is Antigenic drift? (in relation to influenza A)
The gradual accumulation of mutations in AA code, changing the form of influenza A –> allowing it to avoid produced antibodies
Why can’t we always fight off influenza?
As we only produce antibodies against the strain of influenza that was present (eg, H1N1)…..and there are many different subtypes of influenza A!!
Influenza is made up of Neuraminidase (11 subtypes) and Hemagluttinin (18 subtypes) Therefore many different combinantions of influenza can be made (eg, H1N2 or H2N3)
Whats the difference between cortisone and cortisol?
Cortisone = Ketone at carbon 11
Cortisol = Alcohol at carbon 11
What must always be present at the 11 position of steroids?
A hydrogen bonding capable molecule (eg, OH/C=O)
What is the most stable ring structure?
6 sided –> Then 5
Whats the difference between pandemic and seasonal influenza?
Pandemic –> When a new strain is formed, in which the body has zero protection against (often from another species). It cannot be predicted!!
Seasonal –> A varient of a previous strain, so a large amount of the population will have some protection
Describe the 2 types of influenza treatments
Adamantes –> These interefere with the M2 (transmembrane) protein of Influenza A, so less can get into host particles
Reduce illness duration by 1 day if taken quickly enough Sadly, there is lots of resistance to these
Neuraminidase Inhibitors –> Similar to adamantes, but less toxic
They are competitive inhibitors of influenza active sites These are active against all strains (A, B and C) and serotypes (eg, H1N1 and H2N3) of influenza
What are the limiting factors of the influenza vaccine?
Growth potential –> of the least avaliable strain Potency
Testing –> Each strain must be tested (which takes time)
Timing of strain selection Licensing –> The annual licence supplement approvment needs to be gained in time for packaging and shippment
What is Zanamivir (Relenza)?
A transition-state analogue
Draw adrenaline
Draw Acetylcholine
What type of molecule is at carbon 9 in steroids?
Especially beclometasone and fluticasone
A halide
Eg, Cl/F
In reference to steroids, what benefit do including esters have?
They are lipophillic, so allow easier crossing of lipid bilayers
And in topical treatments it increases the skin penetration
How are all of the carbons in a steroid labelled?
Name some examples of drugs that will chelate di-valent ions?
Tetracyclines (eg, doxycycline)
Isonazid
Adriamycin
Techincially any drug that has two polar groups next to each other(ish)
