Combo chemistry

Question 1

Combinatorial chemistry

Answer 1

• Original meaning- Production of large numbers of compounds in the form of mixtures or combinations
• The sets of compounds produced from an automated synthetic run are known as compound libraries
• Look for a hit- if not then you can discard all of those compounds
• Only workes in certain biological assays

Question 2

Combinatorial chemistry

Answer 2

• Current meaning- any form of high-throughput or automated synthesis
• E.g. parallel synthesis, matrix synthesis
• Generally, meany discrete compounds (only one compound per reaction vessel)

Question 3

Mixtures or discrete compounds

Answer 3

• The early work produced mixture libraries =>
• Useful only if the bio-assay can cope with mixtures of compounds
• Can an individual compound in a mixture be present at a high enough concentration to exert its biological effect
• If a mixture proves to be active, can you figure out which compound(s) in the mixture is (are) active
• These days libraries of discrete compounds are preferred

Question 4

The products could be made

Answer 4

• Individually in parallel
• In mixtures
• Using either automated solutions or solid phase techniques
• Whatever the technique used the common denominator is the productivity has been amplified beyond the levels that have been routine for the last 100 years

Question 5

Before the 1980’s

Answer 5

• Rate of synthesis of compounds= rate of testing of compounds
• It took about 10,000-15,000 new compounds synthesised and tested before a drug was found
• A medicinal chemist would commonly prepare about 50 compounds per year for testing
• Thus 1 drug= 300 chemists

Question 6

During 80s

Answer 6

• Automation was introduced into biological screening
• Suddenly, 50 compounds per year from chemist was not enough

Question 7

History- other driving factors

Answer 7

• Generics =>
• Price restraints =>
• Increasing R&D costs =>
• All need to increase productivity
  
  • Make and test compounds faster and cheaper
  • Reduce project cost

Question 8

During 1990’s

Answer 8

• Automation was introduced into chemical synthesis
• Driven by pragmatism (forget high purity criteria)
• Facilitated by solid phase chemistry- breakthrough chemistry- chromatography

Question 9

Libary design- negative sense

Answer 9

• Lipinski’s rule of 5
• Designing out bad compounds

Question 10

Problems with success

Answer 10

• 10,000 compounds per day tested in 50 screens
  
  • 500,000 new data points per day
• They had a data overload with a lot of it not being useful
• Too many compounds which could be made even with advanced robotics
• Data handling bottleneck
• Large numbers of active compounds not possessing drug-like properties
• Make fewer better compounds

Question 11

Why do compounds fail in development

Answer 11

• Poor biopharmaceutical properties- 41%
• Lack of efficacy- 31%
• Toxicity- 22%
• Market reasons- 6%

Question 12

Fail fast, fail cheaply

Answer 12

• ADME screens
• Toxicity
  
  • These are physical screens
  • Compound is required
  • Time-consuming
  • Resource-intensive
    
    • Great interest in computation of molecular and biological properties and drug-likness

Question 13

Lipinski rule of 5

Answer 13

• Compounds with 2 or more of the following characteristics are flagged as being likely to have poor oral bioavailability
  
  • More than 5 H-bond donors
  • MW >500
  • LogP >5
  • H-bond acceptors >10
  • Here O and N => H-bond acceptors
  • N-H and O-H => H-bond donors

Question 14

Rule of 5- easily done

Computerised filter

Answer 14

• Select out those compounds which violate Lipinski rule of 5
• Other computer-based property estimations may be included
• E.g. LD₅₀ >100mg/Kg
• Ames mutagenicity probability <0.9 (remove polycyclic and activated aromatics)
• Rotatable bonds less than ~8

Question 15

Libary design- In a positive sense

Answer 15

• You can use your chemical knowledge to design a chemical synthesis using a range of commercially available building blocks
• Some of the compounds produced will have similar properties, some will be quite different
• Which compound should be included in your library of compounds

Question 16

Combinational library design

Answer 16

• Virtual combinatorial libraries are collections of compounds that could be synthesised from a set of available reactants
  
  • These libraries can reach sizes too large to synthesise
  • Diversity techniques may be used to select which members will be actually synthesised
  • The purpose for which the library is being assembled and nature of the chemistries required will determine the strategy to implement
  • The library may be
    
    • Diverse
    • Focussed
    • Complementary to an existing library

Question 17

Which compounds should be included in your library of compounds

Answer 17

• That depends upon what the library is for: lead discovery or lead optimisation
• Whatever the use will need to make a selection of compounds
• How should the compounds be chosen

Question 18

What is the purpose of the compound library

Answer 18

Question 19

What is the purpose of the compound libary

Answer 19

• Lead discovery- the compound library should be highly diverse
• Lead optimisations- the compound library should have constrained (Targeted) diversity
• The actual situation will depend upon the information available at the time and is likely to be somewhere between the two extremes
• The degree of diversity required is inversely related to the quantity of knowledge known about the targets for which those libraries are designed

Question 20

Using the concept of pharmacophores to make compound choices

Answer 20

• The term pharmacophore is used to describe the types of atoms and their geometric arrangements which are common across an active set of molecules
• Pharmacophore => the minimum 3D geometrical arrangement of functional groups necessary for activity
  
  • Usually, there are only 3 or 4 atoms involved in a pharmacophore, forming hydrogen bonds or other similar, energetically favourable interactions with the receptor
  • Peptide is not usually worth considering in pharmacophore identification studies because of the multitude of H-bonds

Question 21

Using the concept of pharmacophores to make compound choices

Answer 21

Question 22

What is the purpose of the compound library

Answer 22

• Lead discovery=> the library of compounds should contain as many pharmacophores as possible
• Typical pharmacophore-based diversity analysis: to include a compound there must be less than
  
  • 8 rotatable bonds (when a flexible molecule binds to a protein to form a bimolecular complex, it will have a larger entropic penalty to pay than a less flexible molecule because of the reduction in conformational degrees of freedom)
  • 10,000 pharmacophores
  • 10% overlap with pharmacophores from previously included compounds

Question 23

Diverse library selection

Answer 23

• Large initial compound set = Diverse selection=> Smaller representative set

Question 24

What is the purpose of the compound library

Lead optimisation

Answer 24

• Most compounds should contain at least the pharmacophore which is though to be necessary for activity
• This assumes that all active compounds act at the same site in the same manner
• If an active pharmacophore exists for the active compounds then it must be one of a subset of pharmacophores which is common across all the active compounds
• Next slide for using this information to search out compounds similar to the active set

Question 25

Process of pharmacophore searching

Answer 25

• Active compound set (lead compounds) =>
• Generate all possible pharmacophores and select those common across the active set =>
• Use the common pharmacophores to search for other possible active compounds in other database=>
• Synthesise and test these