Choose a target and find hit/lead compounds II

Question 1

Lead compound

Answer 1

• Highly active on the target effected on the disease has drug like properties
• chemically stable and easily synthesised
• Low side effects and toxicity
• Factors that enable compounds ability to reach the target pKa properties

Question 2

Structure activity relationship

Answer 2

• Iterative systamatic changing of structure to investigate effects on activity
• Tolerated or non-tolerated to allow for macrophore identification
• One modifcation at a time to see if nessecary

Question 3

Drug like properties

Answer 3

• Water solubility and Log(P) balance between the two
• Molecular weight
• Avoid presence of Pan-Assay-Interferance-Compound effect biological screening lead to false positive
• Avoid presence of toxicophoric groups - Induce toxicity reactive amine structures, hydroxylation of amide structures

Question 4

Lipinski’s rule of 5

Answer 4

• Predictors of drug likeliness for sucessful oral drugs
• Relative molecular weight <500
• Number of H-bonds donating equal or <5 OH NH
• Number of H-bonds accepting equal or <10 C=O COOR
• LogP <5 partition coefficent lipophilic to pass membrane but not too lipophilic must be distributed

Rare to 2 point but can break 1

Question 5

Drug optimisation

Answer 5

• Interaction of drug with its target - better activity and selectivity
• Alkyl substituent, add aromatic ring chain extension, isoesters and bio-isoesters
• Optimisation by NMR or CADD

Question 6

Isoesters

Answer 6

• Shares same valency size and similar chemically and physically

Question 7

Bioisoesters

Answer 7

• Retain similar biological properties
• Use lead modifications to obtain ADMET properties
• Can replace O with CH2 NH and S similar size but different electronic properties
• OH replace with CH3 NH2 SH and F

Effects lipophilicity

Question 8

What makes a good drug?

Answer 8

• What drug does to the body and what body does to the drug
• Effective at targeting disease non toxic - Pharmacodynamics
• Absorbed well in body, able to reach target easily and not modified too quickly - Pharmacokenetics

Question 9

Optimisation hydrophilic

Answer 9

• Solubility of ADME properties too polar or hydrophilic doesn’t cross cell membrane
• Polar functional group makes them plasma prone to binding and rapid excreation

Question 10

Optimisation hydrophobic

Answer 10

• Dissolve in fat globules poor absorbtion
• Poor solubilty in the blood low circulation levels toxic metabolites are formed from hydrophobic drugs

Question 11

Changing functional groups

Answer 11

• Changing alcohol into ether
• Carboxylic acid into ester to decrease polarity
• Addition of alkyl groups N-alkyl to vary pKa
• Addition of bioisoesters to increase polarity

Question 12

How do you make drugs more resistant to degradation

Answer 12

• More resistant to hydrolysis and drug metabolism therefore increases activity

Question 13

Steric shield

Answer 13

• Protection of susceptible groups by adding steric shield to hinder approach of nucleophile to susceptible group

Question 14

Electronic effects of bioesters

Answer 14

• Stablise liable functional groups using bioisoester

Question 15

Metabolic blockers

Answer 15

• Small groups at site where polar groups are added during metabolism to stop it and prolong drug activity

Question 16

Deutrium replacing H

Answer 16

• Strong C-D block metabolism covalen bont twice as strong block metabolic metablosim

Question 17

Removal or replacement of susceptible metabolic groups

Answer 17

• CH3 on aromatic ring is oxidised by COOH causes quick elimination
• Replacement with halogens such as F oxidation potantial of methyl groups make it more resistant to oxidisation

Question 18

Flourine optimisation

Answer 18

• Similar size to H increase lipophilicity and reduces pKa altering conformation
• Electron conformation effects potency
• lipophilicity effects absorbtion and distribution

Question 19

Targeting drugs tumour

Answer 19

• Attaching active drug to important building block molecule
• Enable active drug to attach to monoclonal antibodies which recognises antigens unique to tumour cell

Question 20

Targeting GI drugs

Answer 20

• Use fully ionised drugs that cannot cross cell membrane

Question 21

Targeting peripheral regions

Answer 21

• Increase the polarity of the drug so it is less likely to cross the blood brain barrier

Question 22

Prodrugs

Answer 22

• Inactive in themselves but converted in the body to the active drug by enzyme
• Improve drug pereability - esters are a prodrug which are N-methylated
• Prolong activity by converting slowly to the active drug
• Masks tocicity and side effects
• Increase water solubility for IV
• Lower water solubilty decrease bad taste

Question 23

How do prodrugs take the drug to the target

Answer 23

• UTI prodrug is stable at a pH above 5
• When UTI is present causes the decrease in pH causing the prodrug to be activated as it degrades

Question 24

Example of prodrug

Answer 24

• Tedizolid - Poor antibiotic not soluable
• The phosphate group increases solubility and absorption
• Valcyclovir vs cyclovir - increased solubilty in val higher availability and ester can be cleaved

Question 25

Quanitative structure activity relationship

Answer 25

• Systemic modification - quantifiable properties molecule is measured and plotted
• Corralation used to predict effect of new modifications
• Identifies the parameters predict the effect