How do drugs work? Part II Flashcards
What are destabilizing non-covalent interactions?
Interactions in which ligand is prevented from binding to target due to steric hindrance caused by bulky group blocking the way to the receptor.
How are destabilising NCIs used?
They allow selection of receptors to bind using molecules that often bind to more diverse receptors. Eg isprenaline resembles adrenaline in structure but can only bind to beta adrenoceptors and not alpha adrenoceptors due to these interactions they experience on alpha adrenoceptors.
What is high energy conformation?
Conformation which requires an input of energy to reach (eg squishing carbon chains together as seen on ACE inhibitor cilazapril)
What must free energy for reaction to be more stable?
-ve
What does -ve enthalpy and entropy favour?
- ve enthalpy favours complex formation
- ve entropy does not favour complex formation.
This can more easily be remembered using the formula for gibb’s free energy:
ΔG =ΔH–TΔS
What happens to entropy with ligand binding?
It decreases due to having to move and rotate less closer to binding site. Conformational entropy is also lost because the molecule does not rotate within the molecule as much.
What kinds of molecules favour ligand binding?
Rigid molecules because they require less change in entropy and so they have a free energy advantage over flexible molecules.
What does the entropy affect drug design?
Most drugs have rigid structures with lots of rings, double bonds, and triple bonds.
What happens when a hydrophobic ligand binds to a hydrophobic receptor?
There is an increase in entropy because the order that was present with water molecules surrounding the binding site had to be displaced and so they lose structure.
What drives the hydrophobic effect?
The increase in entropy created by displacement of water and hydrophilic molecules from hydrophobic surface.
What happens to hydrophobic effect with increase in distance?
There is an exponential decay in strength with an increase in distance.
Why are drugs not made extremely hydrophobic?
Because then that would make them lose specificity due to becoming attracted to more hydrophobic molecules.
Why does the entropy not increase if the hydrophobic molecules are being clumped together?
The solvent itself increases in entropy. Thus, water molecules are displaced creating more entropy due to more units being in a state of disorder.
The hydrophobic molecules do get a decrease in entropy as well but the net change on the entire system is an increase in entropy due to the larger number of water molecules compared to the large hydrophobic molecules.
What kind of molecules are cell membrane targetting drugs?
Molecules with large numbers of hydrophobic regions to associate with cell membrane. (Eg ergoserol binding - amphotericin) which forms a pore in fungal cell membrane)
How does amphotericin work?
Contains large hydrophobic region and large amphiphilic region which binds to ergoserol in fungal cell membrane causing it to form a pore which makes membrane more permeable.
Humans have a different molecule in the cell membrane (cholesterol no ergosterol).
