assignment 3 Flashcards
describe electrostatics in terms of what the interaction consists of, relative strength, and any special considerations for drug design
Electrostatics are the attraction between + and – charges. They are nondirectional, and their strength depends on the distance between the
charges. They give stronger interactions in non-polar environments
describe hydrogen bonds in terms of what the interaction consists of, relative strength, and any special considerations for drug design
Hydrogen bonds are specialized dipole-dipole interactions involving
slightly positive hydrogens attached to heteroatoms (N or O) forming a
dipole interaction with unpaired electrons of nearby electron donors (N
or O). Their strength depends on the distance between the electron pair
donor and the hydrogen. These forces are directional, and get stronger as
the X-H bond aligns with the orbital holding the unpaired electrons of the
acceptor. They give stronger interactions in non-polar environments
describe dipole-dipole in terms of what the interaction consists of, relative strength, and any special considerations for drug design
Dipole-dipole interactions involving the attractions between partial
positive and partial negative charges. These partial charges are usually
the result of differences in electronegativity between atoms of different
type bonded together. Slightly positive atoms are attracted to slightly
negative ones. The strength of the interaction depends on the distance
between the atoms. These forces are non-directional. They give stronger
interactions in non-polar environments
describe van der waals in terms of what the interaction consists of, relative strength, and any special considerations for drug design
Van der Waals interactions are small, temporary, induced dipole-dipole
interactions between molecules. Random movement of electrons within
molecules create areas of positive and negative charge. These small
charges tend to attract or repulse electrons in nearby molecules, thus
creating complimentary opposite charges that attract each other. These
forces are non-directional. They give stronger interactions as the contact
surface areas between molecules increases.
why do solvent exposed binding sits on the surface of enzymes provide weaker binding for drugs than binding “pockets” do
Interactions on the surface of proteins can become surrounded by water
molecules. These water molecules become attracted to the dipole
interactions between the drug and the protein, which has the effect of
diluting the attraction between the drug and protein. Inside binding pockets,
the attractive forces between drug and protein are limited to each other.
there are no extra water molecules around to participate, which strengthens
the interaction between the drug and protein.
what is meant by the term “drug-like”? what is the major challenge in making a “drug-like” drug
Drug like refers to molecular properties which make a drug convenient for a
patient to use. These properties create drugs which are “user friendly”. The
major challenge in doing this is that this process involves properties which work in “opposite” directions (lipophilicity and hydrophilicity). Difficult to
improve one property without making the other worse.
most drugs approved for human use are acids or bases. how can acid/base behaviour be a beneficial property for drugs
acids and bases are usually charged at physiological pH
- this makes them soluble in water
- acid base equilibria makes them easy to convert to neutral forms to pass
biological membranes
most drugs approved for human use are acids or bases. why are bases more common than acids
- phosphate groups on outside of membranes are negative
- this creates region of negative charge very close to the surface of the
membrane - acids are usually negative at pH 7.4
- negatively charged molecules repelled at the surface of membranes, this
makes it more difficult for them to pass through
most drugs approved for human use are acids or bases. Molecules that carry permanent charges are often a problem for drug
delivery. Why do you think this is?
permanent charges cannot pass membranes well, lipophilic environment
of the membrane (50 angstroms wide) does not tolerate strongly charged
molecules
- charged molecules more easily removed by the kidney
most drugs approved for human use are acids or bases. why are weak acids or bases generally better drugs than strong acids or bases
The pKa of weak acids and bases tend to have values near 7. This means
that at pH 7, there will always be a small amount of the neutral form of
the drug present. This increases the rate at which the drug can pass
through membranes. Strong acids and bases tend to be charged almost all
the time. The amounts of neutral form drug are so small that intake into
membranes becomes very slow
what are the main component parts in a membrane phospholipid
- head group
- phosphate
- glycerol
- fatty acid esters
for hydrogen bond donors, describe the criteria applied and provide a brief explanation of why the rule helps to predict oral bioavailability.
Want fewer than 5 HBD’s. HBD’s help solubilize molecules, but if this number
gets too large, the molecules become less lipophilic and cannot cross
membranes
for hydrogen bond acceptors, describe the criteria applied and provide a brief explanation of why the rule helps to predict oral bioavailability.
Want fewer than 10 HBA’s. HBA’s help solubilize molecules, but if this
number gets too large, the molecules become less lipophilic and cannot cross
membranes
for molecular weight, describe the criteria applied and provide a brief explanation of why the rule helps to predict oral bioavailability.
Want MW less than 500. Large molecules tend to be less soluble in water
(create too large a cavity) and less able to pass biological membranes (too big
to slide between the fatty acid chains).
for LogP, describe the criteria applied and provide a brief explanation of why the rule helps to predict oral bioavailability.
Want CLogP less than 5, or MLogP less than 4.15. As log P gets larger,
molecules become less water soluble.
