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DONE Drug Design and Discovery > Ian Eggleston - Combinatorial Chemistry 2 > Flashcards

Ian Eggleston - Combinatorial Chemistry 2 Flashcards

1
Q

What is being described?
Solid phase or Solution phase chemistry?

  • Easy to drive reactions to completion
  • Good product purity
  • Large number of steps
  • Automation available
  • Chemistry limited
  • Quantities limited
  • Cleavage step
  • High capacity for ‘pools’
A

Solid phase chemistry

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2
Q

Equipment for solution and solid phase library synthesis can be split into two categories.

  • One of these categories is ‘Independent modular equipment’
  • What is this?
A
  • Synth split into sub-procedures
  • Addition of reagents and incubation with reagents
  • More flexible with respect to chemistry that can be done and throughput
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3
Q

Equipment for solution and solid phase library synthesis can be split into two categories.

  • One of these categories is ‘Fully automated units’
  • What are these?
A
  • Perform whole synthesis without manual interference
  • More prone to breakdown
  • Less manual labour, less time, less resources
  • Restricted with chemistry that can be used
  • More complex
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4
Q

Name some equipment which is only used if either solid/solution phase chemistry is needed

A
  • Solution - Parallel combinatorial chemistry in solution
  • Stock solutions of reactants need to be dispensed by liquid handling units into reactors of different formats
  • Solid phase chemistry (or supported reagents)
  • Need additional wash and filtration capabilities
  • Both cases
  • Equipment for solvent evaporation in reactors need (either integrated or separate module)
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5
Q

Describe the steps used in ‘SynCar’ extraction (Aventis Pharma)

A

1) Load
2) Synthesis
3) Extraction - Extraction
4) Evaporation
5) Weighing
6) Filtration
7) Solid Phase Extraction
8) HPLC-MS

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6
Q

Give some benefits and limitations of creating large libraries using combinatorial synthesis

A

Benefits:

  • Large numbers of compounds produced
  • Cover many permutations
  • Comprehensive template 3D space coverage
  • Good value for money - efficient use of time and reagents

Limitations:

  • Frequent deconvolution issues
  • Small quantities of each produced
  • Almost exclusively solid phase
  • Limited chemistry available
  • Validation time is long
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7
Q

Give some benefits and limitations of creating small focused libraries using combinatorial synthesis

A

Benefits:

  • Generally 1 compound/reactor (parallel synth)
  • Solution/solid phase compatibility
  • More chemistry applicable
  • Makes more of each compound

Limitations:

  • Potentially more expensive
  • May leave diversity gaps
  • Only cover small regions of 3D space for a given template
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8
Q

What are the aims of lead discovery?

A
  • To generate a large number of compounds
  • To generate a diverse range of compounds
  • Maximise chances of finding a lead compound to fit binding site
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9
Q

Why are spider like scaffolds good for exploring conformational space?

A
  • Variation of func groups around whole molecule

- Increase chances of finding binding interactions

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10
Q

What are privileged scaffolds?

A
  • Common scaffolds or molecular templates in medicinal chemistry
  • Able to provide potent and selective ligands for range of biological targets through modification of func groups
  • Often exhibit good drug like properties
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11
Q

What is lipinski’s rule of 5?

A
  • MW of less than or equal to 500
  • Less than or equal to 5 HBD (OH or NH)
  • Less than or equal to 10 HBA (sum of H and O’s)
  • Log P less than or equal to 5
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12
Q

What compounds may be exceptions to Lipinskis rule of 5?

A
  • Compounds that are actively transported and natural products
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13
Q

What are the properties of leadlikeness?

- Extension to Lipinski’s ideas

A

RULE OF THREE!

  • MW less than 300
  • LogP less than 3
  • Less than or equal to 3 HBD
  • Less than or equal to 3 HBA
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14
Q

What is the reasoning behind making criteria for lead likeness rather than just using Lipinski’s rules?

A
  • Lead optimisation usually results in increased mol weights and lipophilicity
  • Therefore, drug discovery should start with lead-like structures that not only meet RO5 but have even tighter specifications
  • Reduce attrition at later stages
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15
Q

What are the advantages of combinatorial chemistry for the medicinal chemist?

A
  • Can accelerate drug discovery process at several stages
  • Cover more pharmaceutically relevant space in one library than by conventional chemistry (lead discovery)
  • Helps rapidly explore active series (SAR)
  • Helps rapidly refine compounds to find best PK profile (lead optimisation)
  • Provides more patent examples than might be obtained from using conventional synthetic methods
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16
Q

What would be the perfect screening programme for drug discovery?

A
  • Unlimited collection of unique compounds
  • Unlimited access to novel, well defined biological targets
  • High speed automation for maximum throughput
  • Unlimited computational resources
17
Q

Why would you automate and miniaturise in HTS?

A 
MINITURISE:
- Speed and cost (cheaper and quicker) as less reagent used and smaller sized plates
AUTOMATE:
- Increase speed of identification of high quality leads
- Reduce errors in...
- Hand held manipulations e.g pipettes
- Liquid handling
- Transfer of microplanes
- Weighting

OVERALL:
Max precision and speed at lower cost

18
Q

When developing an assay, what is used to ensure quality and comparability between plates in separate runs?

A
  • Internal control wells
19
Q

What are some technical considerations with assay development?

A
  • High standards of reproducibility, scalability, compatibility with automation needed
  • Detection methods include - UV visible absorbance, fluorescence spectroscopy, automated cellular fluorescence imaging
  • Each plate needs internal control wells to ensure quality and comparability between plates in separate runs
  • Quality of assay determined by Z factor (depends on response associated with positive and negative controls )
  • High quality = Z’ greater than 0.5
20
Q

When might Affinity based screening be used?

e.g methods such as MS, NMR and X-ray crystallography?

A
  • Use NMR, MS, X-ray crystallography

- Required for HT screening of very small, lead like fragments, which may be very weak ligands for a target of interest

DONE Drug Design and Discovery (9 decks)

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