20- sar part 6 molecular mods

Question 1

what are the four steps of drug optimization

Answer 1

• Start with lead structure
• Make related compounds (1 factor at a time, only changing electronic properties)
• Measure the potency and properties of each compound
• Use patterns in the data to identify

Question 2

what are the seven techniques of molecular modification

Answer 2

• Additions/deletions
• Substitutions (functional group)
• Chain extension/contraction
• Ring expansion/contraction
• Ring variations (substitute some of the atoms in the rings for another one)
• Simplifications (deleting something)
• Rigidification (rigid = more potent)

Question 3

what are isosteres

Answer 3

Functional group replacements where it has the same kind of activity in the molecule as the original group → produces similar shape/size/biological activity

Question 4

what are classical isosteres

Answer 4

• Atoms or groups that have the same valency and similar size
• Help determine if groups are important for binding or not
  
  • Alter properties in a very controlled way
  • very similar sterics and distributions of electrons
  • conservateive charges = easier to figure out whats happening

Question 5

what are non-classical isosteres/bio-isosteres

Answer 5

• Atoms or groups that have similar chemical properties
  
  • Differ in overall electronics and sterics
  • structures can be extremely different
  • geometry and electronic layout are usually similar

Question 6

what is tetrazol

Answer 6

• 4 N atoms, the one connected to an H is involved in the aromaticity of the ring
• the H is easily removeable, see it used a lot in drugs

Question 7

what is the purpose of chain extensions/contractions

Answer 7

try to line up or create pharmacophore

Question 8

what is the goldilocks rule

Answer 8

in SAR, whenever possible try to work in groups of 3 (one too small, too big, then just right)

Question 9

what is structure simplification and when is it done

Answer 9

• Remove parts that do not affect potency
• Remove stereocenters
• done after you identify a pharmacophore

Question 10

explain the cocaine example with structure simplification

Answer 10

• cocaine used as a pain kill, shows anesthetic tendencies
• caused by the distance between the N and the COO-ring
• developed procaine and lidocaine by simplifying cocaine structure

Question 11

why are racemates easier to make and test

Answer 11

• since biological molecules are chiral, you must test both configurations
• consider enantiomers as separate compounds

Question 12

what are pharmacophores?

Answer 12

• Groups which are important for activity
  
  • Includes their 3-D spatial relationships
  • how to molecule binds to the target
  • gives you a template to design future molecules

Question 13

what is the slang and formal definition of pharmacophore?

Answer 13

slang: Describe groups that physically interact with biological molecule
formal: binding group plus their overall relationships