4 Flashcards
(21 cards)
what is combinatorial chemistry
- prepare molecules in every combination in the same reaction pot
what is a disadvantage of combinatorial chemistry
- due to them using the same reagent and reacting at the same time they have limited structural diversity
what should you use to maximize combinatorial chemistry
you should use rational drug design and know what you’re looking for
2 benefits of combinatorial chemistry
uses reliable reactions to minimize side products and also makes many products fast
3 steps to combinatorial chemistry
- starting reagent is attached to solid beads/polymer support
- reaction occurs
- beads are washed off to remove side products
4 advantages of combinatorial chemistry
- diff starting materials can be linked to separate beads, all beads can be exposed to the same reagent at the same time
- since bound to solid support excess reagent or unbound by-products can be removed by washing
- in addition excess reagent can be used
- intermediates in a reaction are bound to bead so don’t need to be purified
how are results processes and what techniques are used
- mixtures of compounds can be separated from the solid support
- then are identified by a series of techniques like liquid chromatography mass spectrometry (LCMS) or high performance liquid chromatography (HPLC)
what is fragment based
small fragments containing active groups can be used instead of whole molecules
how is fragment based processed
structural methods like Xray crystallography and NMR used to find out how chemical fragments bind
what 2 rational does fragment combine and 2 benefits
- gives greater access to chemical space and links rational design with high-throughput screening
- more efficient then traditional chemical synthesis and more access to chemicals space
how does fragment increase chemical space
- because molecules are ridged even if they have the correct groups that could be in the wrong position
- thus if you add fragments they have no restraints so they will fit where they an bind
3 steps of fragment
- soaking target with fragments from screen
- whether the fragments bind is determined using structural methods
- lead compound then produces based on fragment binding
what techniques are used along side fragment to analyze results and what methods can it be combined with
- use structural techniques like X-ray crystallography, NMR or even mass spectroscopy
- can be combined with computational methods to improve design of molecules
3 ways this data can be used to make full molecules
linking, growing, merging
what is linking
- structural date is used to see where the function groups bind the length between them
- now you just link the fragments together in the same shape
- two fragments are soaked into a binding site which are then joined together to produce a single compound
what is growing
add on additional molecules to fill up space to maximise binding until no more can bind to target site
what is merging
- find 2 or more fragments that bind to different sections of the pocket
- make a molecule that contains both binding groups to maximize both binding areas instead of just 1
6 rules fragments must follow and what is the rule of 3
- 8-18 non-H atoms
rule of 3
1. mass of ca 300 or less
2. 3 or less HBD
3. 3 or less HBA
4. LogP = 3
5. on average 3 or less rotatable bonds
4 pros to fragment
- systematic approach
- gives access to a far larger section of chemical; space than other methods
- rapid via high throughput methods
- combines rational and high throughput approach
3 cons of fragments
- requires structural data
- needs access top high-tech techniques
- need structural date of your target or closely related biomolecules
why can IR not be used for fragment
no cuz not structural technique and does not tell you any info on how molecule binds in binding site
