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Drug Design

Geometrical isomerism

Chirality

Chiral auxiliaries synthesis

Polarity & Modifications

Ring strain

Combinatorial chemistry

Parallel synthesis
Geometrical Isomerism
Against
cancer
Inactive
DNA without
CIS-platin
DNA with
CIS-platin
Chirality
Thalidomide
Why chirality matters
Asymmetric Synthesis
Synthesis of One Enantiomer using a Chiral Auxiliary
O
O
O
chemical steps
OH
NH
2
OH
OH
NH
2
Bothhandedforms of product
(racemic mixture; 1:1mixtureof enantiomers)
Put auxiliary on
O
O
chemical steps
O
takeauxiliary off
OH
NH
2
NH
2
O
HN
[
Chiral Auxiliary
:
O
]
Polarity

MORPHINE

HEROINE

-OH polar groups

Ester less-polar groups

Not lipid soluble

Lipid soluble

Hard to get in brain

Easy to get in brain
Modifying polarity
Amine + HCl => hydrochloride salt (ionic, more soluble)
Prozac
Modifying polarity
Carb. Acid + NaOH => Sodium salt (ionic, more soluble)
Aspirin
Esters as prodrugs
Prodrug
Drug
Fatty
barrier
esterase
O
C
R
O
C
C
R
O
O
Prodrug
O
OH
O
Drug
O
O
C
C
R
O
Ester masking polar groups
allowing passage through
fatty cell membranes
esterase
R
OH
Ring strain
Active ring
with strain
because of
different
hybridizations
Bind to cell wall synthesis enzyme
What is Combinatorial Chemistry?
• Is an approach that provides efficient
synthesis of a large collection of molecules
• Screening of libraries of related compounds to
isolate the molecule of desirable property
• Used in both academia and industries to
generate huge libraries of compounds that
have important biological properties
Combinatorial Chemistry
Combinatorial Library
•
•
•
•
4 monomers
Nn Combinations
44 = 256
tetramers
Solid Phase Synthesis
resin +
monomer
shake
wash
wash
resin
cleavage
Split-Mix Process
tag each bead!
Mix-Split
Couple
Mix-Split
Couple
33= 27
Solid Phase Library
In 1991s, Houghten & Lam: synthesis of a huge peptide library
20 amino acids
Solid-phase synthesis
202 = 400 dipeptides
DNA: fully automatic (solution)
peptide
203 = 8000 tripeptides
204
= 160,000 tetrapeptides
carbohydrate
small molecule (drug-like)
ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by solid
phase synthesis
Parallel synthesis

On a teflon reaction block

Large number of wells

Add different parts at each step

Common conditions
12-well reaction block
Add Scaffold to each well
S
S
S
S
S
S
S
S
S
S
S
S
Wells after Addition of first
reagent
SA
SB
SC
SD
SA
SB
SC
SD
SA
SB
SC
SD
There are now twelve different
products
SA1
SB1
SC1
SD1
SA2
SB2
SC2
SD2
SA3
SB3
SC3
SD3
Computer aided drug design