IC8 Strategies for Structural Modifications in SAR Studies Flashcards
What are the 3 approaches in structural modifications?
Explain what they are and when will they be used?
Approach 1: Analogue (similar complexity)
- Specific changes
- End product: broadly similar compounds
- Need to show great ↑ efficacy and ↓ in ADR for drug to be approved
Approach 2: Adding Groups (conjunctive approach)
- Entirely new functional group to create new interactions
- ↑ MW and usually ↑ cLogP
Approach 3: Simplification (Disjunctive approach)
- Remove unnecessary groups
- Create simpler compounds while retaining key interactions
What are the different types of strategies for structural modifications? (12)
- Variation of substituents (on aromatic rings)
- Chain extension/contraction (+alkyl substitution)
- Ring expansion/contraction
- Ring variation
- Ring fusion (+benzologue)
- Extension of structure
- Isosteric replacement
- Simplification of the structure
- Stereoisomers
- Ring equivalents
- Vinyl groups and vinlogues
What is alkyl substitution?
What are the effects?
Alkyl substitution:
Explore effect of chain length + bulk / depth and width of binding site
- Changing R groups occur through different chemical pathways
- R groups can be methyl, ethyl, propyl tert-butyl
Effects:
- ↑ binding interaction, ↑ binding affinity,
↑ binding selectivity - Inform about the hydrophobicity of the pocket
What is varying substituents on aromatic ring? What are the effects?
Varying substituents on Aromatic ring
Explore effect of different types + position of groups
- Groups can be OH, NH2, halogens, alkyl
- Positions → affect shape/structure → interaction and activity
- E.g. previously planar structure → when add group to ortho, it could lead to steric hindrance and repulsion, thus twist the structure to non-planar to relieve steric hindrance → in turn too bulky to fit into the target site
Effects:
- ↑ binding interaction
What is vinyl groups and vinylogues? What are the effects?
Vinyl groups and vinylogues
H2C=CHR (ethylene) Alpha, beta unsaturated ketone; enol
C=C-C=O C=C-C-OH
- Others – arenologues, cyclovinylogues
Effects:
- Enol – acidic
- Enone – affect metabolism of parent group e.g. Michael Addition: B-carbon is subjected to attack by GSH becos it is more e-deficient
What are ring variations?
What are their effects?
Ring Variations (substitution)
Different ring size, different number and position of heteroatoms in the ring
- Create me too drugs/analogues of similar biological activities and structures
Effects:
- ↑ selectivity
- ↑ activity, ↓ ADR
E.g. change phenyl ring to heterocycle, adds 1 H bond interaction
What are the ring equivalents?
Ring equivalents
- Carbocyclic rings: cyclohexane, cyclopropane, steroid, triterpene
- Aryl rings: benzene, naphthalene, phenanthrene
- Heterocyclic rings: pyridine, pyrimidine, furan, thiophen, quinolone, indole
Rings can be flat/bulky, aromatic/non, hetero/cyclo, acidic/basic
What is ring expansion?
Ring expansion/contraction
Increase the ring by 1 unit (not a functional grp)
- ↑ flexibility (rotating bonds), ↓ constraint (better angles)
- Tell us the capacity of the binding site (there’s a limit to how much it can expand)
Effects:
- E.g. ↑ ring size, ↓ IC50 (↑inhibitory effect)
What is the classic bioisostere replacement?
Classic Bioisosteric replacement
Replace functional groups with other functional group that has similar biological properties (at the same position)
- Monovalent bioisosteres
o F, H
o OH, NH
o F, OH, NH, CH3 can replace H
o OH, SH - Bivalent, trivalent, tetrasubstituted atoms
Effects:
Change natural substrates to drugs
What is ring fusion? What are the effects?
Ring fusion
Usually if from single bond to ring fused between other rings → rigidification, less rotation and more constraints → affects the way drug binds to target
- Can be carbocycles, aryl rings, heterocycles etc.
Effects:
- ↑ interaction
- ↑ specificity & selectivity
- ↑ hydrophobic interaction, ↑ binding affinity
What are the benzologue? What are the effects?
Benzologue (type of ring fusion)
Add benzene ring via fusion
- Explore linear or angular benzologues (shape)
Effects:
- ↑ hydrophobic interaction, ↑binding affinity
What is extension of structure? What are the effects?
Extension of structure
Add another functional group
- explore new interactions sites
Effects:
- ↑ binding interaction
- Alkyl groups – ↑ hydrophobic interaction
- OH, amine, amide, acid, phenol – ↑ H bond/ionic bond
- Often converts agonist to antagonist, substrate to inhibitor
What is simplification of structure? What are the pros and cons or this?
Simplification of structure Usually on lead compounds from natural sources
- Since they are slow, tedious and expensive to produce
- Remove non-essential parts, retain essential parts
Effects/Pros:
- Easier to produce in large quantities
Cons:
- Simplified molecule binds differently to target
- Decrease target selectivity
- Loss desirable pharm activity
- Increase ADR
What to look out for for the stereoselectivity of biologically active compounds?
Stereoselectivity in biologically active compounds
Check for chiral centres in compound
Enantiomers can have different biological responses
3 point contact model:
- Hydrophobic interaction
- H bond
- Ionic interaction
- Since the enantiomers are non-superimposable, there will be 2 groups that do not bind to the sites/correct sites
How to calculate selectivity?
Selectivity calculation: selectivity = less active/more active
- Must be the same value e.g. IC50, Ki, ED50
- E.g. in Ki values → 514/1.8 =285 → Drug A is 285x more selective and active than Drug B
