topic 1 - intro and intermolecular reactions Flashcards
how do you create a medicine?
misbehaving biochemistry - introduce chemical influence - normal chemistry.
a chemical which changes biochemistry is called a DRUG.
how do you influence biochemistry?
- To change biochemistry we need to act on it at the chemical level
- We need some kind of interaction with a biomolecule
why is Covalent bonding rarely used?
Most drugs do not make covalent bonds with their biomolecular targets
Making a covalent bond would require high reactivity
High reactivity makes it hard to be selective
Exceptions include cis-platin which cross-links DNA to kill cancer cells (with significant side effects).
why are electrostatic interactions common?
These result from the attraction between molecules bearing opposite electronic charges.
Strong ionic interactions can contribute very strongly to binding.
Proteins contain both CO2- and NH3+ residues and these may be present at the binding site to interact with oppositely charged groups on the drug
what are ion-ion interactions?
effectively stronger in a hydrophobic environment than a polar environment due to competition by water.
non directional.
usually the binding site is more hydrophobic than the surface so this increases the effect of an ionic interaction.
loss of ion bond strength with a separation is less than that for other intermolecular interactions so if an ionic bond is present it is likely to be the most important interaction as the drug enters the binding site.
what are ion-dipole interactions?
less electronegative C
more electronegative O
higher electron density on O = dipole
ion dipole interactions can control the orientation of molecules.
what are dipole dipole interactions?
dipoles antiparallel (aligned in opposite directions) favoured.
dipoles parallel (aligned in the same direction) disfavoured
dipole dipole interactions can control the orientation of molecules.
what are hydrogen bonds?
A hydrogen bond is an electrostatic interaction between a polarised (δ+) proton (H) with a nearby (δ-) atom bearing a lone pair
The Donor provides the H, while the Acceptor provides an electron pair
Most hydrogen bonds vary between 16-60 kJ mol -1
(~10x less than a covalent bond)
what are Van Der Waals interactions / London Dispersion interactions?
There are always transient areas of high and low electron densities leading to temporary dipoles
So dipole in one molecule can lead to induced dipoles in neighbouring molecules
This is an attractive interaction
they have an instantaneous dipole, a induced dipole and no dipole. and an electrostatic interaction.
Formed from instantaneous dipoles
Found everywhere molecules are close
Weaker than other electrostatic interactions
Hence, more significant in non-polar (hydrophobic) environments
what holds together non polar molecules?
oils, waxes and liquid nitrogen
what is the hydrophobic effect : D entropy?
Water molecules are in a highly disordered state. Each molecule maximises H-Bonds to other molecules
of water.
When a hydrophobic drug is placed into water, the structure of the water around the drug is more ordered. This allows the H2O-H2O H-bonds to be maintained. This leads to lower entropy and is not favoured.
Hydrophobic interaction between protein and drug is favoured by higher entropy. Bulk water returns to less ordered state Water molecules may be expelled from being bound in active site.
in addition, enthalpy gains due to new interactions between the protein and drug. and between water and water may also be favourable.
hydrophobic effect continued
Entropy gains are achieved when water molecules are displaced from ‘active site’, and return to a more random state.
Each -(CH2)- group can contribute >1 kJ/mol towards binding
Each -Ph ring can contribute >2 kJ/mol towards binding
These effects are additive and hence hydrophobic bonding
can make a very high contribution to binding
Close fitting of molecules is especially important – is it the right
size and shape?
Drugs, in general, are hydrophobic molecules The binding sites of proteins are also hydrophobic in character Thus a mutual attraction can result (like binds like).
What drives this attraction?
Enthalpy gains may result from van der Waals bonding, displaced water
Entropy gains may result from displaced water molecules
what is pi pi stacking (TT TT)?
π-π stacking is a phenomenon arising from a combination of forces
Aromatic systems are often observed
sitting on top of each other (stacking)
These arise in simple molecules mainly due to the efficient packing arrangement maximising dispersion interactions
If the aromatic units are polarised, electrostatic interactions contribute (e.g. dipole-dipole)
In water the stacking lets hydrophobic units efficiently expel water
