P1 - DNA as a Drug Target Flashcards
Describe how non specific drugs work
Bind targets outside of cells (e.g. on membrane, GI tract, skin)
Different structures can have similar pharmacological effects
No defined molecular target
Give an example of a class of non specific drugs and name some examples
General anaesthetics (act on neuronal plasma membranes) e.g. alcohols, nitrous oxide, halogenated hydrocarbons, noble gases, ethers, cyclic hydrocarbons
Describe how specific drugs work and use an example to illustrate this
Have a defined 3D structure
Direct interaction between molecule and target
Minor changes to the structure have a huge impact on activity (e.g. thalidomide enantiomers)
Name an example of an antifungal medication that targets lipids, and explain how it works
Amphotericin B
Very potent antifungal, treats fungal meningitis
Has a hydrophobic region (heptene) and hydrophilic region (lots of OH groups) linked by COOH
The COOH binds OH on ergosterol (fungal cell membranes have ergosterol, animal cells have cholesterol)
6 molecules form a polar pore in the membrane allowing ions to leak out
Has lesser effects on cholesterol, so has side effects on kidneys
Name an example of an antibiotic medication that targets lipids, and explain how it works
Valinomycin
Used to treat severe acute respiratory syndrome
Donut shaped molecule with hydrophobic groups outside and hydrophilic groups inside
Forms pore big enough for potassium
Why does the valinomycin pore allow potassium through but not sodium, which is a smaller molecule?
The charge of sodium is felt more strongly, more strongly binds water molecules so it cannot get through the pore
What are the 4 types of drug that target DNA?
Groove binders
Intercalators
Alkylating Agents
DNA cleavage agents
Name an example of a DNA groove binder, and explain how it works
Distamycin
Anticancer drug
Slightly curved structure that fits in the minor groove
Binds AT rich regions using hydrogen bonding and hydrophobic interactions
Alters DNA conformation to inhibit transcription
Name an example of a DNA intercalator, and explain how it works
Acridines such as Amsacrine
Used to treat leukaemia
Usually flat molecules such as polycyclic aromatics
Forms hydrophobic interactions with heteroaromatic part of bases
Leads to DNA unwinding, prevent transctipion/translation, causes apoptosis
What are the 3 classes of DNA intercalator?
Acridines
Actinomycins
Anthracyclines
How do DNA alkylating agents work?
They are strongly electrophilic
Form covalent bonds with nucleophilic sites on adenine and guanine
Irreversibly inhibits transcription and translation, leading to apoptosis
What are the 4 types of DNA alkylating agents?
Nitrogen mustard
Ethyleneimines
Methanesulfonates
Platinum complexes
Name an example of a nitrogen mustard, and explain how it works
Cyclophosphamide
Prodrug, metabolised into active form phosphamide mustard by phosphoamidase, which is produce by tumours
Alkylates guanine N7
Forms both INTERstrand and INTRAstrand cross links
Name an example of an ethyleneimine, and explain how it works
Diaziquone
Similar structure to a nitrogen mustard, but extended to make them more lipophilic so they can pass the BBB and be used to treat brain tumours
Name an example of a methanesulfonate, and explain how it works
Busulfan
Alkylates guanine N7
Creates INTRAstrand cross links
Treats chronic myeloid leukaemia
