med chem drug design

Question 1

what are the properties of a good drug?

Answer 1

• 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).

Question 2

what determines what drugs are required for binding?

Answer 2

•Incremental structural changes to determine which groups are required for binding

Question 3

how do alcohols bind with ethers?

Answer 3

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

Question 4

what kind of interactions do the aromactic ring have?

Answer 4

good interaction- pi stacking

(flat )hphobic binding region

Question 5

what kind of interaction foes a cyclohexane have?

Answer 5

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.

Question 6

how do amines bind?

Answer 6

• Aromatic amines do not usually use lone pair as H-bond acceptor.
• Lone pair is also unavailable in salts.

Question 7

what difference would changing an aromatic ring to an alkane?

Answer 7

would not be sterically the same

Question 8

what happens if you have a carbonyl?

Answer 8

big dipole dipole movement- may not line up

- big energy difference between the two

Question 9

what happens to an amine in a physiological environment?

Answer 9

it will be protinated- extra H bond donor

Question 10

how can you probe amide binding?

Answer 10

has to be a primary or secondary amine to go to a amide cannot be tertiary

Question 11

what happens if you have a beta lactam?

Answer 11

the formation of a new covalent bond will collapse to give ester

Question 12

how do you probe carboxylic acids and esters?

Answer 12

CA would be ionised aand h bond acceptors and attract with +ve charge
ester in non-conventional way- nucleophillic serine

Question 13

what are ither common functional group interactions?

Answer 13

• 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

Question 14

how do molecules interact with networks and tautomerism?

Answer 14

• 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

Question 15

what is an isosteres?

Answer 15

• Something in mol you can replace with something same size and shape

Question 16

what is an expanion?

Answer 16

putting new group on

usually something in the middle to make the interaction more optimal

Question 17

what is contraction?

Answer 17

opposite to expansion squeeze things together

Question 18

what is a ring variation?

Answer 18

• Change one to another- often to give better pharmacokinetic type properties- adding h bond donners/taking away

Question 19

what do isosteres do?

Answer 19

keep size constant while varying electronics eg H to F

Question 20

what do non-classical isosteres do?

Answer 20

Non-classical isosteres retain key physical or chemical properties.

Question 21

what do bioisostere do?

Answer 21

Bioisostere is a general term for replacements leading to retention of activity while removing undersirable properties.

Question 22

what is a simplification strategy?

Answer 22

extraneous sections can be systematically removed
.•Allows modulation of ADME properties while retaining activity
.•Also allows for more economical industrial production

Question 23

what is not desirable in simplification?

Answer 23

chiral centres

Question 24

how do you deal with chirality?

Answer 24

• 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.

Question 25

what is ridigification and why is it useful?

Answer 25

stop molecules from being flezible-improves potency and seletivity

Question 26

what does conformation blocking do?

Answer 26

• May either promote or disrupt binding.
• Molecule (I) active against dopamine D3receptor as antagonist.
• Conformationally restricted analogue (II) displays significantly reduced activity

Question 27

why would you add or remove a hydrocarbon?

Answer 27

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.

Question 28

what are some other ways to modulate polarity?

Answer 28

adding H groups

low aq solubility

Question 29

do ethers have low or high water solubility

Answer 29

low

Question 30

how do you modulate polarity?

Answer 30

bioisosterism

- this increases resistance to degradation

Question 31

how do you increase metabolic stability?

Answer 31

change ch3 to c02h or ch20h

- needs to be prone to oxidation by the body

Question 32

what are prodrugs?

Answer 32

• Inactive compounds that become active after metabolic transformation, or external stimulus, eg photodynamic therapy.
• Modulate acid sensitivity, membrane permeability, taste, and duration of action.

Question 33

what can also be used as a prodrug strategy?

Answer 33

de methylation and decarboxylation

Question 34

how do you prolong a drugs activity?

Answer 34

•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

Question 35

how you reduce toxicity and s.e?

Answer 35

•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

Question 36

how do you reduce water solubility of a drug?

Answer 36

• 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.

Question 37

how do you increase the water solubility of a drug?

Answer 37

• 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.

Question 38

how do you moduft a peptide?

Answer 38

• 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

Question 39

how do you increase a drugs effectiveness?

Answer 39

expose residue remains solvated

Question 40

how do you modify a phosphate backbone?

Answer 40

• Flip around where base attaches to it- rna/dna

- Can incorporate new things

Question 41

what are modulations for oligonucleotides?

Answer 41

•Oligos used in antisense therapies

.•Natural oligos suffer from nuclease degradation.

•Poor permeability too, due to size and charge.