Small molecule recognition and DNA binders

Question 1

Examples of small molecules

Answer 1

Chemical messengers
Co-factors
Drugs
Poisons
Toxins
Pollutants

Question 2

Receptors for small molecules can act as…

Answer 2

…
Receptors
Sequestering agents i.e. very tight binding, strong interaction, molecule not released once bound
Sensors i.e. produce a measurable response/signals after an interaction with a small molecule

Question 3

Uses of DNA binders

Answer 3

Signal the presence of errors in DNA e.g. for diagnosis of genetic disorders
Identify specific DNA conformations e.g G-quadruplexes (more common in cancer)
Target faulty DNA and induce apoptosis i.e. anti-cancer drugs!

Question 4

Modes of DNA binding

Answer 4

Coordination e.g. to N in bases, like cis-platin
Pi-pi interactions e.g. intercalators that bind in the minor groove
Electrostatic interactions (because DNA is negatively charged)

Question 5

Why are H-bond interactions less useful for DNA binders?

Answer 5

Because DNA is in water

However some H-bonding agents do exist e.g. pyrrole-imidazole polyamides

Question 6

G-quadruplexes

Answer 6

Present in telomeres and in the promoter region of certain oncogenes
Self-assembled, guanine-rich, 4-stranded DNA structures
Play key roles in biological processes

Question 7

G-tetrad

Answer 7

= 4 guanines H-bonded to one another

3 tetrads stack on top of one another, with a monovalent cation (Na+/K+) between each tetrad

Question 8

3 forms of G-quadruplexes

Answer 8

Parallel
Anti-parallel
(3+1) hybrid

G-quadruplexes are dynamic so can swap between each of these, meaning drugs that bind to G-quadruplexes must also be flexible and able to adopt to the different conformations

Question 9

Characterisation of G-quadruplexes

Answer 9

NMR

X-ray crystal structures

Question 10

Why is small molecule recognition of nerve gases difficult?

Answer 10

Because nerve gases are small, simple molecules with limited functionality

Question 11

How do nerve gases exert their effects on the body?

Answer 11

By inhibiting acetylcholine esterase

Question 12

Development of sensors for nerve gases

Answer 12

Use nerve gas simulants (actually pesticides) e.g. DMMP, TEP
These will react with a probe that will then fluoresce
This provides a method for sensing the presence of a nerve gas

Question 13

Carcinogens

Answer 13

Aromatic molecules that can react with DNA, leading to mutations

Question 14

Properties of carcinogens

Answer 14

Stable and hydrophobic (i.e. insoluble in water) so are difficult to eliminate from the body and are stored in body fat

Question 15

Ideal properties of a carcinogen receptor

Answer 15

Curvature - to form a cavity
Hydrophobic/solvophobic cavity
Host is soluble in the desired solvent e.g. water
Binding of guest to host lowers the solubility of the host-guest complex so it crashes out and can be filtered off

Question 16

Calixarenes

Answer 16

Derived from a phenol and an aldehyde

Question 17

Resorcinarenes

Answer 17

Derived from 1,3-dihydroxybenzene and an aldehyde

A type of calixarene

Question 18

Properties of calixarenes/resorcinarenes

Answer 18

Bucket/cone shape
Intramolecular H-bonds between the OH groups stabilise the conformation
Good for trapping molecules of medium hydrophobicity

Question 19

Cyclodextrins

Answer 19

Cyclic oligosaccharides (6-8 glucoses)
Most common and most well-studied hosts
Cheap and commercially available
Fully saturated
Intramolecular H-bonding
Rigid
Curvature
Water soluble but have hydrophobic cavity
Slow-release and compound-delivery agents§

Question 20

Shape of cyclodextrins

Answer 20

Buckets
Primary hydroxyl groups at bottom of bucket
Secondary hydroxyl groups at top (rim) of bucket

Question 21

Packing of cyclodextrins

Answer 21

Can pack in different ways in the solid state
Head-to-head channel type
Head-to-tail channel type
Cage type
Layer type
Layer type composed of beta-CD dimers

Question 22

Cucurbituril

Answer 22

Macrocyclic molecules made of glycoluril monomers linked by methylene bridges
Hydrophobic cavity
Carbonyl of urea provides water solubility