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 Asymmetric Synthesis Synthesis of One Enantiomer using a Chiral Auxiliary [ ] Chiral Auxiliary :

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 polarity Amine + HCl => hydrochloride salt (ionic, more soluble)‏ Prozac

Modifying polarity Carb. Acid + NaOH => Sodium salt (ionic, more soluble)‏ Aspirin

Esters as prodrugs Ester masking polar groups allowing passage through fatty cell membranes

with strain because of different hybridizations 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 resin cleavage wash

Split-Mix Process 33= 27 tag each bead! Mix-Split Couple Mix-Split

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 carbohydrate small molecule (drug-like)‏ 204 = 160,000 tetrapeptides 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

Wells after Addition of first reagent SB SC SD SA SB SC SD SA SD SB SC

There are now twelve different products SA1 SB1 SC1 SD1 SA2 SB2 SC2 SD2 SA3 SD3 SB3 SC3

Computer aided drug design