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Drug Disco > Comb Chem 2 > Flashcards

Comb Chem 2 Flashcards

0
Q

Independent modular is…

A

synthesis is split into subprocedures

such as handle, incubate, filtrate etc.

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1
Q

Two basic cat for equipment

A

Independent modular

Fully automated units

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2
Q

Advantages of independent modular 2

A

This is more flexible in terms of chemistry and throughput
as we can combine different bits of kit to fit the problem.
Most appropriate when making large numbers if compounds for library

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3
Q

Automated is…

A

perform whole synthesis without manual interference

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4
Q

Pro of manual

A

save valuable time and resources overall

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5
Q

Con of manual 3

A

More complex, less flexible, more prone to breakdown,

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6
Q

Parallel combinatorial chemistry in solution equip considerations

A

stock solutions of reactants need to be dispensed by liquid handling units into reactors of different format (12, 24, 96-well)

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7
Q

Considerations for solid and solution

A

equipment for evaporation of solvent in the reactors is needed (either integrated or separate module).

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8
Q

Consideration for solid phase equipment

A

apparatus needs additional wash and filtration capabilities

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9
Q

SynCar

A

Fully automated set up for synth of a library — the kind of thing found in big pharma

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10
Q

With full automation what sort of rate is possible

A

Hundreds of compounds in 24hours

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11
Q

Detection methods for HT online purification a ANC characterisation5

A

• UV absorbance
• Evaporative light scattering
• Chemiluminscent nitrogen
• MS ***
• NMR

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12
Q

Quality of compounds in HT screening data depends on 2

A

quality of the compounds being tested

likelihood of “false positives” and “false negatives”

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13
Q

multi-channel HPLC

A

Increased complexity of HT synthesis has also made (HT) purification by chromatography an essential part of modern drug discovery

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14
Q

Steps to fully automated purification

A

Library - single/multicolumn HPLC - UV detection - compound collection in multiple tubes - Evaporation, reformatting (sorting into 96 well plates) - Confirmatory MS analysis of selected samples

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15
Q

Fully automatised purification a can do…. Compounds in a day

A

300

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16
Q

UV can be combined with

A

Ms to allow mass triggered detection

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17
Q

HPLC uses what as Ca mobile phase?

What sort of flow rates and gradients?

A 
Short columns (2-5 cm, 2-5 mm id), high flow  rates, rapid gradients (1-3 min), Supercritical Fluid Chromatography
CO2 as mobile phase
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18
Q

4 benefits of large libraries

A
  • large no of compounds
  • many permutations
  • comprehensive template 3d coverage
  • good value for money
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19
Q

Cons of large libraries 5

A
  • Deconvolution problems
  • small quantities produced
  • almost exclusively solid phase
  • limited chem avail
  • validation time is long (need to find out what compounds in the mixture are active - need to combine with high throughput screening)
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20
Q

Small (focused library benifits?

A
  • 1 compound/reactor
  • solid/solution phase compatibility
  • more chemistry applicable
  • make more of each compound ( can test more than once)
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21
Q

Limitations of focused lib

A
  • Potentially more expensive
  • may leave diversity gaps
  • only conver small regions of 3D space for given template
22
Q

Small vs big libraries

A

We prefer small, higher quality (not just in terms of purity but it terms of structure)
Cut down numbers in the early stages

23
Q

Most common and synthetically straight forward compounds to produce in libraries

A

Linear (peptides or peptiodes)

24
Q

Diversity in linear molecules comes from

A

Side chains

25
Q

Other compounds produced

A
  • branched (2 reacting groups on a building block, funcitonalised independently)
  • template or scaffold
26
Q

What types of structures are best

A

In the earliest stage of drug disco we have some sort of drug target. We want to find compounds that interact and give the right biological activity.
To maximise chance of binding we probably want a structure that will fit that model and building blocks that combines together will give that model.

Once done we then want to see want parts f this molecule are useful and what has no function. Alter the drug.

To summarise spider like structures are probably the best for exploring space and for a larger library in early stages of drug disco.

27
Q

Spider like allows…

A

Spider-like” scaffolds that allow/involve variation of functional groups around the whole molecule should be best for exploring conformational space as they increase chances of finding suitable binding interactions

28
Q

Three aims for 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

29
Q

Privileged scaffolds

A

Common scaffolds/templates in medicinal chemistry that provide potential and effecting ligands for range of targets by modifying functional group

30
Q

Eg of privileged scaffolds

A

BZ
Betalactams
Pyridine a

31
Q

Other advantage of privileged scaffolds

A

Often exhibit drug like properties

32
Q

Lipinkis rule of five

A
  • MW ≤ 500 - Lipophilicity (log P) ≤ 5 - Sum of H-bond donors ≤ 5 - Sum of H-bond acceptors ≤ 10
33
Q

Diversity is irrelevant if the library is ….

A

Insoluble ( not drug like )

34
Q

Exceptions to solubility problem (2)

A

Drugs that are activity transported and natural prod

35
Q

Rule of three rationale

A

Lead optimisation usually results in increased molecular weight and lipophilicity. Therefore, drug discovery should start, if possible, with lead-like structures that not only meet RO5, but have even tighter specifications -therefore carefully select libraries and building blocks early to avoid attrition at later stage

36
Q

Advantages of comb chem

A
  • accelerates process at several stages
  • possible to cover more pharmaceutically relevant space in a lib than by conventional methods
  • rapid exploration of SAR
  • helps refine compounds for best PK profile
  • Provides many more patent examples than might be obtained from using conventional synthetic methods
37
Q

The Perfect Screening Programme for Drug Discovery: 4

A

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

38
Q

We need screening methods that can keep up with the production of leads such as

A

Good biological assays
High-quality HTS compound libraries
Ability to test libraries in assays in a fast, cost-effective manner

39
Q

Summarise the evolution of HTS

A

HTS development in late 90’s driven by quantity and speed, but beset with problems due to impurities and false positives ⇒ smarter library design
Post-2002, quality of libraries ↑ and size ↓, but speed still essential

40
Q

Why miniaturisation?

A

Save time and money

41
Q

Why automisation? 2

A

Increased speed and identification of high quality leads

Reduce errors

42
Q

What sort of errors does automisation reduce?

A
  • Hand-held manipulations (e.g. pipettes) - Liquid handling, by e.g. using robotics - Transfer of microplates - Sample storage, preparation/weighing, dispensing - System-wide information handling
43
Q

Automated experimental setup and data entry achieved with…

A

barcoding
Results processed and stored centrally.

Overall: Maximum precision and speed at a lower cost

44
Q

Further minaturisation?

A

For further miniaturization, microfluidic technologies are required (also a potential approach for parallel synthesis – “lab on a chip)

45
Q

Assays require 4

A

High standards of reproducibility/scalability/compatibility
automation
Each plate must contain controls

46
Q

Typical detection methods…

A

uv-visible absorbance:fluorescence spectroscopy

automated cellular fluorescence imaging

47
Q

Want factor determines the quality of an assay

What is a good number

A

Z factor

Z>o.5

48
Q

Affinity based screening eg

A

MS (using immobilised proteins), NMR and X-ray crystallography

49
Q

Affinity based is required by …

A

Required for (HT) screening of very small, lead-like fragments, which may be very weak ligands for a target of interest “Fragment-based drug discovery”

50
Q

“off the shelf” library

A

Produced by specialist companies such as maybridge

Offer compounds for screening

51
Q

HTS services and libraries “to order” are also available from companies and academic institutions:

A

University of Dundee

52
Q

Successful stories 3

A

Maraviroc: chemokine receptor antagonist (HIV and AIDS)
Gleevec : small molecule inhibitor of Bcr-Abl tyrosine kinase (leukemia)
GNf-2 : an allosteric inhibitor of Bcr-Abl dependent cell proliferation

Drug Disco (12 decks)

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