Drug Design Optimizing Target Interactions Chapter 13 Part 3

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

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

2. Vary alkyl substituents Rationale: Vary length and bulk of alkyl group to introduce selectivity Binding region for N Receptor 1 Receptor 2

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

2. Vary alkyl substituents Adrenaline Salbutamol (Ventolin) (Anti-asthmatic) Propranolol (b-Blocker)

a-Adrenoceptor H-Bonding region Ionic bonding Van der Waals

a-Adrenoceptor ADRENALINE

a-Adrenoceptor

b-Adrenoceptor ADRENALINE

b-Adrenoceptor SALBUTAMOL

b-Adrenoceptor

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor

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.

2. Vary alkyl substituents Methods

2. Vary alkyl substituents Methods

3. Vary aryl substituents Vary substituents Vary substitution pattern Weak H-Bond Binding Region (H-Bond) (for Y) Strong H-Bond (increased activity)

3. Vary aryl substituents Vary substituents Vary substitution pattern Benzopyrans Anti-arrhythmic activity best when substituent is at 7-position

Inductive electron withdrawing effect 3. Vary aryl substituents Vary substituents Vary substitution pattern Para substitution: Electron withdrawing effect due to resonance + inductive effects leading to a weaker base 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

4. Extension - extra functional groups Rationale: To explore target binding site for further binding regions to achieve additional binding interactions RECEPTOR RECEPTOR Extra functional group Unused binding region DRUG DRUG Drug Extension Binding regions Binding group

4. Extension - extra functional groups Example: ACE Inhibitors Hydrophobic pocket Vacant EXTENSION Hydrophobic pocket Binding site Binding site

4. Extension - extra functional groups Example: Nerve gases and medicines Sarin (nerve gas) Ecothiopate (medicine) Notes: Extension - addition of quaternary nitrogen Extra ionic bonding interaction Increased selectivity for cholinergic receptor Mimics quaternary nitrogen of acetylcholine Acetylcholine

4. Extension - extra functional groups Example: Second-generation anti-impotence drugs Viagra Notes: Extension - addition of pyridine ring Extra van der Waals interactions and HBA Increased target selectivity

4. Extension - extra functional groups Example: Antagonists from agonists Propranolol (b-Blocker) Adrenaline Cimetidine (Tagamet) (Anti-ulcer) Histamine

5. Chain extension / contraction Rationale: Useful if a chain is present connecting two binding groups Vary length of chain to optimise interactions Weak interaction Strong interaction A B Chain extension A B RECEPTOR RECEPTOR Binding regions Binding groups A & B

5. Chain extension / contraction Example: N-Phenethylmorphine Binding group Optimum chain length = 2

Better overlap with hydrophobic interactions 6. Ring expansion / contraction Rationale: To improve overlap of binding groups with their binding regions R Ring expansion R Better overlap with hydrophobic interactions Hydrophobic regions

Carboxylate ion out of range 6. Ring expansion / contraction Vary n to vary ring size Example: Binding regions Binding site Binding site Two interactions Carboxylate ion out of range Three interactions Increased binding

7. Ring variations Rationale: Replace aromatic/heterocyclic rings with other ring systems Often done for patent reasons General structure for NSAIDS Core scaffold

7. Ring variations Rationale: Sometimes results in improved properties Example: UK-46245 Improved selectivity Ring variation Structure I (Antifungal agent) UK-46245 Improved selectivity Ring variation Structure I (Antifungal agent)

7. Ring variations Example - Nevirapine (antiviral agent) Additional binding group

Selective for b-adrenoceptors over a-adrenoreceptors 7. Ring variations Example - Pronethalol (b-blocker) Selective for b-adrenoceptors over a-adrenoreceptors

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

8. Isosteres and bio-isosteres Useful for SAR Propranolol (b-blocker) Propranolol (b-blocker) Notes Replacing OCH2 with CH=CH, SCH2, CH2CH2 eliminates activity Replacing OCH2 with NHCH2 retains activity Implies O involved in binding (HBA)

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 Sultopride DU 122290 DU 122290 Pyrrole ring = bio-isostere for amide group Improved selectivity for D3 receptor over D2 receptor

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

9. Simplification Methods: Retain pharmacophore Remove unnecessary functional groups

9. Simplification Methods: Remove excess rings Example: Excess functional groups Excess ring

9. Simplification Methods: Remove asymmetric center Asymmetric center

9. Simplification Methods: Simplify in stages to avoid oversimplification Pharmacophore Notes: Simplification does not mean ‘pruning groups’ off the lead compound Compounds usually made by total synthesis

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9. Simplification Example: Important binding groups retained Pharmacophore Important binding groups retained Unnecessary ester removed Complex ring system removed

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

INT115 Target binding site

INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT116 Target binding site

Rotatable bonds INT117 Target binding site

Rotatable bonds INT118 Different binding site leading to side effects

9. Simplification Oversimplification of opioids

MORPHINE C C O C C C C MOR062.WAV N SIMPLIFICATION

LEVORPHANOL C C O C C C C MOR064.WAV N SIMPLIFICATION

LEVORPHANOL C C O C C C C MOR064.WAV N SIMPLIFICATION

METAZOCINE C C O C C C C MOR065.WAV N SIMPLIFICATION

C C O C C C C MOR065.WAV N OVERSIMPLIFICATION

TYRAMINE C C O C C C C MOR065.WAV N OVERSIMPLIFICATION

AMPHETAMINE C C O C C C C MOR065.WAV N OVERSIMPLIFICATION

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

10. Rigidification RECEPTOR 2 RECEPTOR 1

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

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

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 Rigidification Rotatable bonds

Rotatable bond INT119

Rotatable bond Ring formation INT120

Ring formation INT120

10. Rigidification Methods - Introduce rigid functional groups

10. Rigidification Analogues Examples Inhibits platelet aggregation Important binding groups Inhibits platelet aggregation Analogues Rigid Rigid

10. Rigidification Examples - Combretastatin (anticancer agent) Rotatable bond Less active More active

10. Rigidification Methods - Steric Blockers Introduce steric block Flexible side chain Introduce steric block Orthogonal rings preferred Coplanarity allowed

10. Rigidification Methods - Steric Blockers Serotonin antagonist Introduce methyl group Steric clash Increase in activity Active conformation retained

10. Rigidification D3 Antagonist Methods – Steric Blockers Steric clash D3 Antagonist Inactive - active conformation disallowed

N CH HN O 3 10. Rigidification Identification of an active conformation by rigidification N CH 3 HN O

N N CH N HN O 3 10. Rigidification Identification of an active conformation by rigidification N N CH 3 N HN O

N N CH N HN O 3 10. Rigidification Identification of an active conformation by rigidification N N CH 3 N HN O

N N CH N HN O 3 10. Rigidification Identification of an active conformation by rigidification N N CH 3 N HN O

N N CH N HN O 3 10. Rigidification Identification of an active conformation by rigidification N N CH 3 N HN O

N N CH N HN O 3 10. Rigidification Identification of an active conformation by rigidification N N CH 3 N HN O

N N CH N HN O 3 10. Rigidification Identification of an active conformation by rigidification N N CH 3 N HN O

10. Rigidification Planar conformation Identification of an active conformation by rigidification Planar conformation

10. Rigidification Orthogonal conformation Identification of an active conformation by rigidification Orthogonal conformation

10. Rigidification Identification of an active conformation by rigidification CYCLISATION

10. Rigidification Identification of an active conformation by rigidification CYCLISATION

10. Rigidification Locked into planar conformation Identification of an active conformation by rigidification CYCLISATION Locked into planar conformation

10. Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE

10. Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE

10. Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE

10. Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE

10. Rigidification Locked into orthogonal conformation Identification of an active conformation by rigidification STERIC HINDRANCE Locked into orthogonal conformation

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