ic8 - strategies for SAR studies Flashcards
what are the approaches and strategies
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
how are alkyl substituents used as probe
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
what kind of substituents can be used on aromatic rings and how may these be used as a probe
substituents can be alkyl, hydroxyl or halogen
can inform about how positional isomers may contribute to binding of a ligand to its binding site
if activity increased due to addition of benzene ring what can be concluded
addition of benzene ring then affinity incr -> likely hydrophobic interaction with target site
if activity increased due to substituents added to form tertiary amine what can be concluded
suggests target site is negatively charged to allow for ionic interactions
what is a vinyl group
alkene group
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
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
what is the process when probing using a ring
when lead has a ring, explore whether expanding or contracting the ring by a unit at a time will affect biological activity
what does it mean to see a bell shaped curve results when exploring the lead through ring contraction/ expansion strategy
the binding site can acommodate up to a certain size
what does an increase in interaction or selectivity mean when a fused ring system is added
the binding site/ selected site has an area preferentially for hydrophobic interaction
what does adding a fused ring system result in
cause rigidity to the structure by introducing constraint (bonds cannot rotate as much)
what is Ki value and what does a lower Ki value mean
Ki is inhibitory constant
better affinity and binding
note to ensure comparing in same units when calculating selectivity using Ki values
what is another consideration when using ring fusion strategy
does the number of atoms in the ring affect affinity to binding site
how might a larger ring compare to a smaller ring
a larger ring is more flexible than smaller ring
what are other values that can be used when calculating selectivity between two binding sites
Ki/ IC50/ EF50
what are benzologues and how might they be used as probes
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
what does it mean to use ring variation as a strategy
lead compound has aromatic carboxyclic or aromatic heterocyclic ring -> replace ring with other aromatic ring system/ different ring size/ different heteroatoms
what are some potential results from using ring variation strategy
improve activity, enhance selectivity, reduced s/e
what is one potential advantage of replacing phenyl ring with a heterocycle (through ring variation strategy)
potential extra H bonding interaction
phenyl means CH3 attached to benzene ring
what is IC50 and what does a lower IC50 value mean
IC50 is half maximal inhibitory constant which measures potency
lower IC50 value means better activity
what are the types of rings and which rings are ring equivalent
carbocyclic rings: cyclohexane, cyclopropane, steroid, triterpene
aryl rings: benzene, napthalene, phenathrene
heterocyclic rings: pyridine, pyrimidine, thophen, furan, quinoline, indole
what does it mean to use the extension of structure strategy and how is it used to probe
addition of another functional group to the lead to probe for extra binding interaction at the target (explore new intermolecular interaction that may result)
what are the types of interaction explored when using the strategy of extending the structure
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
what is the strategy of extending the structure mostly used for
to convert agonist into antagonist of receptor or substrate to inhibitor of enzyme
what does it mean by isosteric replacement
involve replacing atoms or groups that are believed to exhibit similar physicochemical properties
list the examples of bioisosteric replacements
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
what does it mean to use the simplification of structure strategy
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
what are the possible disadvantages of oversimplification from simpifying the structure
loss of desirable pharmacological activity
binds differently to target
incr in s/e or toxicity
reduce target selectivity
what is the three point contact model
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
taking into account the three point contact model, what are the three sites for adrenaline
- acceptor donor/ hydrophobic interaction between aromatic ring of adrenaline and an aromatic ring of the receptor protein
- H bond at alcoholic hydroxyl
- ionic bond between protonated amino group and an aspartic or glutamic carboxylic group of the receptor
what happens when the drug interacts with the target and what is the conformation in which the drug binds to the target called
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
