Thermodynamics

Question 1

Explain the effects of entropy and enthalpy

Answer 1

in order for the interaction between ligand and protein to be favourable, balance between the two must be favourable. Negative enthalpic changes include loss of ligand water interactions, loss of protein water interactions, and energetic changes in protein/ligand. Negative entropic changes include loss f conformational flexibility in protein or ligand. Entropic gain would be caused by desolvation of ligands and enthalpic gain caused by formation of bonds with protein

Question 2

Describe the binding of hydrophobic and hydrophilic compounds

Answer 2

hydrophilic binding is driven by enthalpic effects, likely to be more specific, compounds have to be optimal for the target as they need to pay energetic price for breaking interactions with water / lipophilic compounds bind mainly through entropic effects, less specific binding, water is the main driving force and compound will bind to higher fraction of proteins

Question 3

Describe the basic structure , function and mechanism of cytochrome p450 enzymes

Answer 3

membrane bound haeme containing proteins coordinating iron at the active site which carry out phase 1 reactions, with oxidations in liver and intestines and reduction and hydrolysis

Question 4

Explain the role of lipophillicity in metabolism

Answer 4

the lower the lipophillicity the better the solubility so the quicker it will be metabolised

Question 5

Describe the reversible and irreversible stages involved in CYP mediated metabolism

Answer 5

drug forming a complex with the cytochrome p450 is a reversible stage however the oxidation of the complex forming a metabolite-CYP complex is irreversible and so is the complex forming the metabolite

Question 6

What is Gibbs free energy and what does it control?

Answer 6

controls thermodynamic solubility ΔG = ΔH – TΔS

Question 7

What does dissolution mean?

Answer 7

means that drug needs to be in solution in order to leave gastric tract

Question 8

What increases the rate of dissolution?

Answer 8

solution dosing, salt forms and use of amorphous solids

Question 9

What delays rate of dissolution?

Answer 9

enteric coating

Question 10

What does the general solubility equation predict?

Answer 10

aq solubility from logP and melting point , it tells you that logS is correlated in a negative sense to MP and logP

Question 11

What does bioavailability account of?

Answer 11

both absorption and removal of drug from first pass

Question 12

More lipophilic drugs are cleared more?

Answer 12

rapidly

Question 13

How is Kox determined?

Answer 13

by reactivity of molecule towards the CYP