what is a drug?
any substance which when absorbed into a living organism may modify one or more of its functions.
interactions between the drug molecule and human body are…
-multifaced
- difficult to model with high accuracy
what is the purpose of lupinski rule of 5?
a set of empirical rules to recognise essential features in orally administrated drugs
what are Lipinski’s rule of 5?
- molecular weight <500amu (atomic mass units)
- logP <5
- <5 H bond doners (sum of NH and OH)
- <10 H bond acceptors (sum of N and O)
- <10 rotational bonds (otherwise absorption and bioavailability are likely to be poor)
what is one of the most important factors affecting biological activity?
molecular size
measuring molecular size of a drug molecule can be hard. what can the molecular size be indicated by?
the molecular weight of drug molecules
an indication of molecular size can also be indicated using what?
- electron density
- polar surface area
- van der waals surface
- molecular refractivity
partition coefficient P is defined as…
P = [x] octanol / [x] aqeous
x = drug
what is logP a measurement of?
a measure of the relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisation.
why is 1-octanol the most frequently used lipid phase in pharmaceutical research?
- it has a polar and non-polar region
- p o/w is fairly easy to measure
- p o/w often correlates well with many biological properties
- it can be predicted fairly accurately using computational models.
what are the majority of drug molecules?
weak acids or bases (sometimes both)
the extent of drug ionisation on the basis of the pH of the solution in which the drug is found can be calculated using…
Henderson-Hasselbalch equation
what does it mean for a compounds logP if the compound can ionise?
its logP will be pH dependant.
what is the distribution coefficient logD?
-is the effective lipophilicity of a compound at a given pH
- is a function of both the lipophilicity of the un-ionised compound and the degree of ionisation
favourable outcomes logP affects?
- increases binding to enzyme/receptor
- increases absorption through membrane
undesirable outcomes of logP?
- decreases aqueous solubility
- increases binding to p450 metabolizing enzymes
- increases binding to blood/tissue proteins meaning less drug free to act
- increases binding to hERG heart ion channel meaning a cardiotoxicity risk.
intermolecular H- bonding between small molecules in diluted aqueous solutions.
virtually non-existent
intramolecular H-bonding in diluted aqeous solutions
more readily formed because they are entropically more favourable as between same molecule rather than 2 different molecules.
how are most oral drugs absorbed?
through the gut wall by passive transcellular absorption
De-solvation and formation of a neutral molecule is unfavourable if…
the compound forms too many hydrogen or ionic bonds with water
Too many hydrogen bond donors or acceptors are undesirable because…
the drug will not easily get from the gut into the blood stream.
(exception = carbohydrates which have special mechanism)
what is a rotational bond?
any single bond which is not in a ring and bound to a nonterminal heavy (non-hydrogen) atom.
excluding amide C-N bonds due to their high rotational energy barrier.
what does the number of rotational bonds influence?
-bioavailability
-binding potency
rotational bonds on entropy.
A molecule will have to adopt a fixed conformation to bind to a macromolecule. This involves a loss in entropy. More rigid molecules (aromatics or conformationally constrained moieties) will pay a lower entropy penalty.
