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

Synthesis of One Enantiomer using a Chiral Auxiliary

OH

Ochemical steps

Put auxiliary on

Ochemical steps

OH

O

OH

O

NH2 NH2

Both handed forms of product(racemic mixture; 1:1 mixture of enantiomers)

OH

O

OH

O

NH2

take auxiliary offO

NH2

HN O

O

Chiral Auxiliary :[ ]

Asymmetric Synthesis

Polarity

MORPHINE -OH polar groups Not lipid soluble Hard to get in brain

HEROINE Ester less-polar groups Lipid soluble Easy to get in brain

Modifying polarityAmine + HCl => hydrochloride salt (ionic, more soluble)

Prozac

Modifying polarityCarb. Acid + NaOH => Sodium salt (ionic, more soluble)

Aspirin

Ester masking polar groupsallowing passage throughfatty cell membranes

CO

O

R

OC

R

O

CO

O

R

OC

R

O

COH

O

OH

Prodrug

Prodrug

Fattybarrier

esterase

esterase

Drug

Drug

Esters as prodrugs

Ring strain

Active ringwith 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

44 = 256 tetramers

Combinatorial Library

4 monomers

••••

Nn Combinations

Combinatorial ChemistryCombinatorial Chemistry

resin +monomer

shakeresin

cleavage

wash

Solid Phase Synthesis

wash

Split-Mix Process

Mix-SplitCouple

Mix-SplitCouple

33= 27tag each bead!

Solid Phase Library

203 = 8000 tripeptides

20 amino acids

202 = 400 dipeptides

204 = 160,000 tetrapeptides

In 1991s, Houghten & Lam: synthesis of a huge peptide library

peptide

DNA: fully automatic (solution)

Solid-phase synthesis

ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by solid phase synthesis

carbohydrate

small molecule (drug-like)

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

SS

S

S

S

S

S

S

S

S

S

S

Wells after Addition of first reagent

SBSA

SA

SA

SB

SB

SC

SC

SC

SD

SD

SD

There are now twelve different products

SB1SA1

SA2

SA3

SB2

SB3

SC2

SC1

SC3

SD1

SD2

SD3

Computer aided drug design