Chapter 13 Part 3

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Drug DesignOptimizing Target Interactions

• Chapter 13 Part 3

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1. Drug design - optimizing binding interactions
Aim - To optimize binding interactions with target
Reasons

• To increase activity and reduce dose levels
• To increase selectivity and reduce side effects

Strategies

• Vary alkyl substituents
• Vary aryl substituents
• Extension
• Chain extensions / contractions
• Ring expansions / contractions
• Ring variation
• Isosteres
• Simplification
• Rigidification

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2. Vary alkyl substituents

• Rationale
• Alkyl group in lead compound may interact with
  hydrophobic
• region in binding site
• Vary length and bulk of group to optimise
  interaction

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2. Vary alkyl substituents
Rationale Vary length and bulk of alkyl group
to introduce selectivity
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2. Vary alkyl substituents
Rationale Vary length and bulk of alkyl group
to introduce selectivity
Example Selectivity of adrenergic agents for
b-adrenoceptors over a-adrenoceptors
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2. Vary alkyl substituents
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a-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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b-Adrenoceptor
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b-Adrenoceptor
SALBUTAMOL
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b-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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a-Adrenoceptor
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2. Vary alkyl substituents

• Synthetic feasibility of analogues
• Feasible to replace alkyl substituents on
  heteroatoms with other alkyl substituents
• Difficult to modify alkyl substituents on the
  carbon skeleton of a lead compound.

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2. Vary alkyl substituents
Methods
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2. Vary alkyl substituents
Methods
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3. Vary aryl substituents
Vary substituents Vary substitution pattern
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3. Vary aryl substituents
Vary substituents Vary substitution pattern
Anti-arrhythmic activity best when substituent is
at 7-position
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3. Vary aryl substituents
Vary substituents Vary substitution pattern
Meta substitution Inductive electron withdrawing
effect

• Notes
• Binding strength of NH2 as HBD affected by
  relative position of NO2
• Stronger when NO2 is at para position

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4. Extension - extra functional groups
Rationale To explore target binding site for
further binding regions to achieve additional
binding interactions
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4. Extension - extra functional groups
Example ACE Inhibitors
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4. Extension - extra functional groups
Example Nerve gases and medicines

• Notes
• Extension - addition of quaternary nitrogen
• Extra ionic bonding interaction
• Increased selectivity for cholinergic receptor
• Mimics quaternary nitrogen of acetylcholine

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4. Extension - extra functional groups
Example Second-generation anti-impotence drugs

• Notes
• Extension - addition of pyridine ring
• Extra van der Waals interactions and HBA
• Increased target selectivity

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4. Extension - extra functional groups
Example Antagonists from agonists
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5. Chain extension / contraction

• Rationale
• Useful if a chain is present connecting two
  binding groups
• Vary length of chain to optimise interactions

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5. Chain extension / contraction
Example N-Phenethylmorphine
Optimum chain length 2
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6. Ring expansion / contraction
Rationale To improve overlap of binding groups
with their binding regions
Better overlap with hydrophobic interactions
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6. Ring expansion / contraction
Vary n to vary ring size
Example
Three interactions Increased binding
Two interactions Carboxylate ion out of range
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7. Ring variations

• Rationale
• Replace aromatic/heterocyclic rings with other
  ring systems
• Often done for patent reasons

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7. Ring variations
Rationale Sometimes results in improved
properties
Example
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7. Ring variations
Example - Nevirapine (antiviral agent)
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7. Ring variations
Example - Pronethalol (b-blocker)
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8. Isosteres and bio-isosteres

• Rationale for isosteres
• Replace a functional group with a group of same
  valency (isostere)
• e.g. OH replaced by SH, NH2, CH3
• O replaced by S, NH, CH2
• Leads to more controlled changes in steric /
  electronic properties
• May affect binding and / or stability

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8. Isosteres and bio-isosteres
Useful for SAR

• Notes
• Replacing OCH2 with CHCH, SCH2, CH2CH2
  eliminates activity
• Replacing OCH2 with NHCH2 retains activity
• Implies O involved in binding (HBA)

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8. Isosteres and bio-isosteres

• Rationale for bio-isosteres
• Replace a functional group with another group
  which retains the same biological activity
• Not necessarily the same valency

Example Antipsychotics
Pyrrole ring bio-isostere for amide group
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9. Simplification

• Rationale
• Lead compounds from natural sources are often
  complex and difficult to synthesize
• Simplifying the molecule makes the synthesis of
  analogues easier, quicker and cheaper
• Simpler structures may fit the binding site
  better and increase activity
• Simpler structures may be more selective and
  less toxic if excess functional groups are
  removed

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9. Simplification

• Methods
• Retain pharmacophore
• Remove unnecessary functional groups

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9. Simplification
Methods
Remove excess rings

• Example

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9. Simplification
Methods
Remove asymmetric center
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9. Simplification
Methods
Simplify in stages to avoid oversimplification

• Notes
• Simplification does not mean pruning groups
  off the lead compound
• Compounds usually made by total synthesis

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9. Simplification
Example
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9. Simplification

• Disadvantages
• Oversimplification may result in decreased
  activity and selectivity
• Simpler molecules have more conformations
• More likely to interact with more than one
  target binding site
• May result in increased side effects

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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Target binding site
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Different binding site leading to side effects
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9. Simplification
Oversimplification of opioids
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MORPHINE
C
C
O
C
C
C
C
N
SIMPLIFICATION
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LEVORPHANOL
C
C
O
C
C
C
C
N
SIMPLIFICATION
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LEVORPHANOL
C
C
O
C
C
C
C
N
SIMPLIFICATION
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METAZOCINE
C
C
O
C
C
C
C
N
SIMPLIFICATION
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C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
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TYRAMINE
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
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AMPHETAMINE
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
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10. Rigidification

• Note
• Endogenous lead compounds are often simple and
  flexible
• Fit several targets due to different active
  conformations
• Results in side effects

• Strategy
• Rigidify molecule to limit conformations -
  conformational restraint
• Increases activity - more chance of desired
  active conformation being present
• Increases selectivity - less chance of undesired
  active conformations
• Disadvantage
• Molecule is more complex and may be more
  difficult to synthesise

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10. Rigidification
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10. Rigidification

• Methods - Introduce rings
• Bonds within ring systems are locked and cannot
  rotate freely
• Test rigid structures to see which ones have
  retained active conformation

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10. Rigidification

• Methods - Introduce rings
• Bonds within ring systems are locked and cannot
  rotate freely
• Test rigid structures to see which ones have
  retained active conformation

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10. Rigidification

• Methods - Introduce rings
• Bonds within ring systems are locked and cannot
  rotate freely
• Test rigid structures to see which ones have
  retained active conformation

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Rotatable bond
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Rotatable bond
Ring formation
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Ring formation
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10. Rigidification
Methods - Introduce rigid functional groups
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10. Rigidification
Examples
Inhibits platelet aggregation
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10. Rigidification
Examples - Combretastatin (anticancer agent)
Less active
More active
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10. Rigidification
Methods - Steric Blockers
Flexible side chain
Coplanarity allowed
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10. Rigidification
Methods - Steric Blockers
Serotonin antagonist
Increase in activity Active conformation retained
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10. Rigidification
Methods Steric Blockers
Inactive - active conformation disallowed
D3 Antagonist
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10. Rigidification
Identification of an active conformation by
rigidification
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10. Rigidification
Identification of an active conformation by
rigidification
N
N
N
HN
O
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10. Rigidification
Identification of an active conformation by
rigidification
N
N
N
HN
O
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10. Rigidification
Identification of an active conformation by
rigidification
N
N
N
HN
O
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10. Rigidification
Identification of an active conformation by
rigidification
N
N
N
HN
O
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10. Rigidification
Identification of an active conformation by
rigidification
N
N
N
HN
O
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10. Rigidification
Identification of an active conformation by
rigidification
N
N
N
HN
O
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10. Rigidification
Identification of an active conformation by
rigidification
Planar conformation
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10. Rigidification
Identification of an active conformation by
rigidification
Orthogonal conformation
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10. Rigidification
Identification of an active conformation by
rigidification
CYCLISATION
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10. Rigidification
Identification of an active conformation by
rigidification
CYCLISATION
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10. Rigidification
Identification of an active conformation by
rigidification
CYCLISATION
Locked into planar conformation
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10. Rigidification
Identification of an active conformation by
rigidification
STERIC HINDRANCE
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10. Rigidification
Identification of an active conformation by
rigidification
STERIC HINDRANCE
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10. Rigidification
Identification of an active conformation by
rigidification
STERIC HINDRANCE
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10. Rigidification
Identification of an active conformation by
rigidification
STERIC HINDRANCE
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10. Rigidification
Identification of an active conformation by
rigidification
STERIC HINDRANCE
Locked into orthogonal conformation
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11. Structure-based drug design
Strategy Carry out drug design based on the
interactions between the lead compound and the
target binding site

• Procedure
• Crystallize target protein with bound ligand
• Acquire structure by X-ray crystallography
• Download to computer for molecular modelling
  studies
• Identify the binding site
• Identify the binding interactions between ligand
  and target
• Identify vacant regions for extra binding
  interactions
• Remove the ligand from the binding site in
  silico
• Fit analogues into the binding site in silico
  to test binding capability
• Identify the most promising analogues
• Synthesise and test for activity
• Crystallise a promising analogue with the target
  protein and repeat the process

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12. De Novo Drug Design
The design of novel agents based on a knowledge
of the target binding site

• Procedure
• Crystallise target protein with bound ligand
• Acquire structure by X-ray crystallography
• Download to computer for molecular modelling
  studies
• Identify the binding site
• Remove the ligand in silico
• Identify potential binding regions in the
  binding site
• Design a lead compound to interact with the
  binding site
• Synthesise the lead compound and test it for
  activity
• Crystallise the lead compound with the target
  protein and identify the actual binding
  interactions
• Optimise by structure-based drug design