med chem drug design Flashcards
what are the properties of a good drug?
- Interact strongly and selectively with its target.
- Have minimal side-effects.
- Be able to be prepared economically.
- Be chemically stable.
- Have acceptable ADME and Toxicity properties (ADMET).
what determines what drugs are required for binding?
•Incremental structural changes to determine which groups are required for binding
how do alcohols bind with ethers?
lone pairs on oxygen- HBA or
H is a HBD
lone pair is less able to interact as H- bond acceptor
steric factors may influence binding
what kind of interactions do the aromactic ring have?
good interaction- pi stacking
(flat )hphobic binding region
what kind of interaction foes a cyclohexane have?
Cyclohexane, similar in size shape but fatter.
Can not squeeze into as tight a space and can not p-stack, charge-transfer, cation-por donor atom-p interact.
how do amines bind?
- Aromatic amines do not usually use lone pair as H-bond acceptor.
- Lone pair is also unavailable in salts.
what difference would changing an aromatic ring to an alkane?
would not be sterically the same
what happens if you have a carbonyl?
big dipole dipole movement- may not line up
- big energy difference between the two
what happens to an amine in a physiological environment?
it will be protinated- extra H bond donor
how can you probe amide binding?
has to be a primary or secondary amine to go to a amide cannot be tertiary
what happens if you have a beta lactam?
the formation of a new covalent bond will collapse to give ester
how do you probe carboxylic acids and esters?
CA would be ionised aand h bond acceptors and attract with +ve charge
ester in non-conventional way- nucleophillic serine
what are ither common functional group interactions?
- Alkyl halides often react with drug targets through nucleophilic substitution.
- Fluorides usually used as an isostere/bioisostere for hydrogen to modulate electronic properties or prevent unwanted ADME effects. C-F bond strong.
- Aryl halides not usually reactive, tune electron density within aromatic ring and modulate logP.
- Thiols often act within drugs to interact with zinc containing proteins. Probe by replacement with OH
how do molecules interact with networks and tautomerism?
- Adenine- h bond acceptors and donors- can move around ring system- don’t know If you have h acceptor or donor
- Thought the active forms- which cant interact with each other- so tried to figure out double helical forms
what is an isosteres?
- Something in mol you can replace with something same size and shape
what is an expanion?
putting new group on
usually something in the middle to make the interaction more optimal
what is contraction?
opposite to expansion squeeze things together
what is a ring variation?
- Change one to another- often to give better pharmacokinetic type properties- adding h bond donners/taking away
what do isosteres do?
keep size constant while varying electronics eg H to F
what do non-classical isosteres do?
Non-classical isosteres retain key physical or chemical properties.
what do bioisostere do?
Bioisostere is a general term for replacements leading to retention of activity while removing undersirable properties.
what is a simplification strategy?
extraneous sections can be systematically removed
.•Allows modulation of ADME properties while retaining activity
.•Also allows for more economical industrial production
what is not desirable in simplification?
chiral centres
how do you deal with chirality?
- Use racemate? Discouraged by regulators. All enantiomers must be fully tested.
- UH 301, enantiomers have opposing agonist and antagonist activity to 5-HT1A.
- Mevinolin displays eight chiral centres. 2nd generation statins, such as HR780 display fewer.
what is ridigification and why is it useful?
stop molecules from being flezible-improves potency and seletivity
what does conformation blocking do?
- May either promote or disrupt binding.
- Molecule (I) active against dopamine D3receptor as antagonist.
- Conformationally restricted analogue (II) displays significantly reduced activity
why would you add or remove a hydrocarbon?
for polarity:
•Too polar not absorbed by stomach or if injected excreted almost immediately.
•Not polar enough, not soluble and will tend to become trapped in fat deposits.
what are some other ways to modulate polarity?
adding H groups
low aq solubility
do ethers have low or high water solubility
low
how do you modulate polarity?
bioisosterism
- this increases resistance to degradation
how do you increase metabolic stability?
change ch3 to c02h or ch20h
- needs to be prone to oxidation by the body
what are prodrugs?
- Inactive compounds that become active after metabolic transformation, or external stimulus, eg photodynamic therapy.
- Modulate acid sensitivity, membrane permeability, taste, and duration of action.
what can also be used as a prodrug strategy?
de methylation and decarboxylation
how do you prolong a drugs activity?
•6-mercatopurine used to suppress immune system following donor grafts.•However, fast elimination limits utility.•Azathioprine solves this by gradually releasing 6-MP in presence of glutathione
how you reduce toxicity and s.e?
•High plasma levels of diazepam after administration causes drowsiness.
•LDZ gradually allows diazepam to be formed in the body, avoiding this issue.
- avoids passing the bbb
how do you reduce water solubility of a drug?
- Parent compound is effective, but is water soluble and has bad taste.
- The esters are relatively insoluble and tasteless but the ester is readily removed once past the tongue.
how do you increase the water solubility of a drug?
- Particularly important for IV use, where high concentrations and small volumes are preferred.
- Antibacterial agent clindamycin causes pain when injected.
- Phosphate prodrug, more soluble, less pain.
how do you moduft a peptide?
- All of amino acids are in L form- change to D form- this may not bind now
- Ring expansion/ contraction etc to get rid of hydroslibe peptides
- Make dipeptide- one less peptide bond
how do you increase a drugs effectiveness?
expose residue remains solvated
how do you modify a phosphate backbone?
- Flip around where base attaches to it- rna/dna
- Can incorporate new things
what are modulations for oligonucleotides?
•Oligos used in antisense therapies
.•Natural oligos suffer from nuclease degradation.
•Poor permeability too, due to size and charge.
