ic8 - strategies for SAR studies

Question 1

what are the approaches and strategies

Answer 1

approaches: analoguing, adding groups, simplification

strategies: variation of substitution, chain extension/ contraction, ring expansion/ contraction, ring variation, ring fusion, extension of structure, isosteric replacement, simplification of structure, stereoisomers

Question 2

how are alkyl substituents used as probe

Answer 2

R groups are used to investigate the effect of chain length and bulk at binding site

if R group interacts with a hydrophobic pocket, a range of R groups will help to probe the depth and width of the pocket

larger groups incr bulkiness which may confer selectivity of drug for the target

Question 3

what kind of substituents can be used on aromatic rings and how may these be used as a probe

Answer 3

substituents can be alkyl, hydroxyl or halogen

can inform about how positional isomers may contribute to binding of a ligand to its binding site

Question 4

if activity increased due to addition of benzene ring what can be concluded

Answer 4

addition of benzene ring then affinity incr -> likely hydrophobic interaction with target site

Question 5

if activity increased due to substituents added to form tertiary amine what can be concluded

Answer 5

suggests target site is negatively charged to allow for ionic interactions

Question 6

what is a vinyl group

Answer 6

alkene group

Question 7

what does the structure become if a double bond becomes conjugated with a carboxyl group vs conjugated with a hydroxyl group and what chemical properties do each of the groups confer

Answer 7

carboxyl group forms enone -> enone is susceptible to reaction in vivo with glutathione (michael addition)

hydroxyl group forms enol -> enol is acidic

if vinyl alcohol (enol) conjugated to carbonyl group -> strongly acidic

Question 8

what is the process when probing using a ring

Answer 8

when lead has a ring, explore whether expanding or contracting the ring by a unit at a time will affect biological activity

Question 9

what does it mean to see a bell shaped curve results when exploring the lead through ring contraction/ expansion strategy

Answer 9

the binding site can acommodate up to a certain size

Question 10

what does an increase in interaction or selectivity mean when a fused ring system is added

Answer 10

the binding site/ selected site has an area preferentially for hydrophobic interaction

Question 11

what does adding a fused ring system result in

Answer 11

cause rigidity to the structure by introducing constraint (bonds cannot rotate as much)

Question 12

what is Ki value and what does a lower Ki value mean

Answer 12

Ki is inhibitory constant

better affinity and binding

note to ensure comparing in same units when calculating selectivity using Ki values

Question 13

what is another consideration when using ring fusion strategy

Answer 13

does the number of atoms in the ring affect affinity to binding site

Question 14

how might a larger ring compare to a smaller ring

Answer 14

a larger ring is more flexible than smaller ring

Question 15

what are other values that can be used when calculating selectivity between two binding sites

Answer 15

Ki/ IC50/ EF50

Question 16

what are benzologues and how might they be used as probes

Answer 16

benzologues are analogues that have benzene ring inserted by fusion into the structure for exploration of potential enhancement in hydrophobic interaction

study linear and angular benzologues

Question 17

what does it mean to use ring variation as a strategy

Answer 17

lead compound has aromatic carboxyclic or aromatic heterocyclic ring -> replace ring with other aromatic ring system/ different ring size/ different heteroatoms

Question 18

what are some potential results from using ring variation strategy

Answer 18

improve activity, enhance selectivity, reduced s/e

Question 19

what is one potential advantage of replacing phenyl ring with a heterocycle (through ring variation strategy)

Answer 19

potential extra H bonding interaction

phenyl means CH3 attached to benzene ring

Question 20

what is IC50 and what does a lower IC50 value mean

Answer 20

IC50 is half maximal inhibitory constant which measures potency

lower IC50 value means better activity

Question 21

what are the types of rings and which rings are ring equivalent

Answer 21

carbocyclic rings: cyclohexane, cyclopropane, steroid, triterpene

aryl rings: benzene, napthalene, phenathrene

heterocyclic rings: pyridine, pyrimidine, thophen, furan, quinoline, indole

Question 22

what does it mean to use the extension of structure strategy and how is it used to probe

Answer 22

addition of another functional group to the lead to probe for extra binding interaction at the target (explore new intermolecular interaction that may result)

Question 23

what are the types of interaction explored when using the strategy of extending the structure

Answer 23

hydrophobic: alkyl groups added to alcohol, phenol, amine or COOH already present in the lead

H bonding or ionic: hydroxyl group, amide, phenol, acid or amine added to lead

Question 24

what is the strategy of extending the structure mostly used for

Answer 24

to convert agonist into antagonist of receptor or substrate to inhibitor of enzyme

Question 25

what does it mean by isosteric replacement

Answer 25

involve replacing atoms or groups that are believed to exhibit similar physicochemical properties

Question 26

list the examples of bioisosteric replacements

Answer 26

monovalent bioisosteres:
i) F, H
ii) OH, NH
iii) F, OH, NH or CH3 for H
iv) SH, OH
v) Cl, Br, CF3

divalent bioisosteres
C=S, C=O, C=NH, C=C

trivalent atoms or groups
C-=H, N-=, P-=, As-=

ring equivalents: benzene, thiophen, pyridine, furan

Question 27

what does it mean to use the simplification of structure strategy

Answer 27

as whole structure may not be necessary for binding to target site and so once essential group in lead determined from SAR studies, the non essential parts may be removed through structural modification then deriving the optimal structures for best biological activity

Question 28

what are the possible disadvantages of oversimplification from simpifying the structure

Answer 28

loss of desirable pharmacological activity
binds differently to target
incr in s/e or toxicity
reduce target selectivity

Question 29

what is the three point contact model

Answer 29

one enantiomer of a chiral substrate binds to a protein simultaneously at three sites while the other enantiomer cannot bind to the same three sites

Question 30

taking into account the three point contact model, what are the three sites for adrenaline

Answer 30

1. acceptor donor/ hydrophobic interaction between aromatic ring of adrenaline and an aromatic ring of the receptor protein
2. H bond at alcoholic hydroxyl
3. ionic bond between protonated amino group and an aspartic or glutamic carboxylic group of the receptor

Question 31

what happens when the drug interacts with the target and what is the conformation in which the drug binds to the target called

Answer 31

there is induced fitting (bc target also made up of different bonds and so there would be rotation until maximal intermolecular forces of attraction to form drug-target complex)

it is called active conformation and if drug cannot form active conformation the target cannot acommodate the drug