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Hugo Kubinyi, www.kubinyi.de

Serendipity andRational Design

Hugo Kubinyi

Germany

E-Mail [email protected] www.kubinyi.de


Heroic Times: Who Is a Good Surgeon ?Davy, 1799: Experiments with laughing gas

First Half of 19th Century: Sniffle parties

Long, 1841-1849: Ether acts as anesthetic

Wells, 1844: Laughing gas acts as anesthetic


Queen Victoria (1819-1901)1853 * Prince Leopold

Davy, 1799: Experiments with laughing gas

First Half of 19th Century: Sniffle parties

Long, 1841-1849: Ether acts as anesthetic

Wells, 1844: Laughing gas acts as anesthetic

Simpson, 1847: Chloroform

Liebreich, 1868/69: Chloral hydrate as „prodrug“ of chloroform

Schmiedeberg, 1885: Urethane as „prodrug“ of ethanol

Dreser, 1899: i-Amyl carbamate (Hedonal)

von Mering 1903: first barbiturate Barbiton (Barbara / Barbara day)

Heroic Times: Who Is a Good Surgeon ?


Chance, Good Luck and the Prepared Mind

Serendipity: Sir Horace Walpole, 1754

As Their Highnesses [re: the Princes of Serendip]travelled, they were always making discoveries, byaccidents and sagacity, of things which they werenot in quest of.

Louis Pasteur, 1854

Dans les champs de l’observation, le hasard ne favoriseque les esprits préparés.

Albert Szent-Györgi (1893-1986)

Discovery consists of seeing what everybody elsehas seen and thinking what nobody else has thought.


Louis Pasteur

(27.12.1822- 28.09.1895)

1848 Prof.in Dijon, Strasbourg, Lille1857 Paris


Mechanical Separation of Sodium Ammonium Tartrate Crystals (Louis Pasteur, 1848)

Only a few compoundscrystallize as separatestereoiso-mers.

Effect only observedat ambienttemperature.

(+) (-)


A. W. Hofmann (1818-1892)

1845: Queen Victoria visits Germany; PrinceAlbert invites AugustWilhelm Hofmannto come to London

1856: Hofmann asks the 18-years old student William H. Perkin to synthesize quinine byoxidation of aniline


A. W. Hofmann (1818-1892) und W. H. Perkin (1838-1907)

1862: Queen Victoria wears a dress in mauve color


N

N

CH3

NH2 NH

CH3

NH2

R = H or methyl

C20H24N2O2

+ H2O3 [O]

[O]+

C10H13N

Mauveine (Mauve)

allyl- toluidine

Quinine

R

N

OH H N

CH

CH2

H

HMeO

Lack of Success in a Quinine Synthesis (1856)


Cl CHCl

Cl

OH

OHHCl

Cl

ClCH2OHCl

Cl

ClOH-

Chloroform Chloral hydrate

metabolic reduction

Trichloroethanol

Urethane,

Barbitone

O

O

NH2R

N

NO

O

O

Et

Et

R = -CH2CH3

R = -CH2CH2CH(CH3)2

Isopentylcarbamate,

H

H

Chloral Hydrate, a Prodrug of Chloroform ?

Urethane, a Prodrug of Ethanol ?


NH CH3

ON

OO

OH

NH CH3

O

OEt Phenacetin

NH2

OEt

NH CH3

O

OH

p-NitrophenolAcetanilide

+-

Paracetamol(Acetaminophen)

toxic metabolite(methemo-globinformation)

Discovery of Acetanilide and Phenacetin


Aspirin®, the Magic Bullett(Felix Hoffmann, 1897)

OCOCH3

COOH

OH

COOH


O

O

OH

OH Phenolphthalein Arsphenamine, E 606(Salvarsan )

x 2 HClAsOH

NH2

As

NH2

OH

Dyestuffs as Drugs

NH2 N N

NH2

SO2NH2

NH2 SO2NH2 NH2 COOH

Sulfamidochrysoidine ("Prontosil rubrum")

Sulfanilamide, an antimetabolite of p-aminobenzoic acid

metabolic degradation


N

SRHN

O

H

COOH

„Penicillin happened, it came out of the blue.“

A. Fleming, 1930


N

NCl

OCl N

N

O

NCH3

Cl ++

CH3NH2 Chlordiazepoxide

--

H

N CH3

OH

NCH3

NaftifineH+

Unexpected Rearrangement Products


wounded frogs

Survival of Frogs in a Septic Environment

Michael A. Zasloff(NIH)

Proc. Nat. Acad. Sci.USA 84, 5449-5453(1987)

Magaininean antibacterial 23-aa peptide, GIGKFLHSAKKFGKAFVGEIMNS(amphipathic helix formation ?),does not induce resistance. A potential acne treatment ?


Serendipitous Drug DiscoveriesAcetanilide, Acetylsalicylic acid, Aminoglutethimide, Amphetamine, Chloral hydrate, Chlordiazepoxide, Chlorpromazine, Cinnarizine, Cisplatin, Clonidine, Cromoglycate, Cyclosporin, Dichloroisoprotere-nol, Dicoumarol, Diethylstilbestrol, Diphenhydramine, Diphenoxylate, Disulfiram, Ether, Etomidate, Griseofulvin, Guanethidine, Haloperidol, Heparin, Imipramine, Iproniazid, Isoniazid, Levamisole, Lithium car-bonate, Lysergide (LSD), Meprobamate, Merbaphen, Methaqualone, Mifepristone, Naftifine, Nalorphine, Nitrogen mustard, Nitroglycerine, Nitrous oxide, Norethynodrel/Mestranol, Penicillin, Pethidine (Meperi-dine), Phenylbutazone, Phenolphthalein, Praziquantel, Prednisone, Propafenone, Sulfamidochrysoidine, Sulfonamides, Tamoxifen, Urethane, Valproic acid, Warfarin.Sweeteners: Saccharin, Cyclamate, AspartameR. M. Roberts, Serendipity - Accidental Discoveries in Science, John Wiley & Sons, New York, 1989.H. Kubinyi, Chance Favors the Prepared Mind. From Serendipity to Rational Drug Design, J. Receptor & Signal Transduction Research 19, 15-39 (1999).


Four Possible Strategies in Research

Rolf Zinkernagel (Nobel prize in Medicine 1996)

No hypotheses,no experiments

No hypotheses,only experiments

Hypotheses butno experiments

Hypotheses andexperiments !


Sources of New Lead StructuresPlant and microbioal natural productsSerendipitous discoveriesRational approaches (endogeneous transmitters)Me too researchIsosteric replacementOptimization of drug side effectsChemogenomics Chemical biologyProdrugs and soft drugsMetabolic switch - rescuing poor leadsChiral switchCombinatorial chemistry / HTSVirtual screeningStructure-based and computer-aided designFragment-based designCombinatorial design H. Kubinyi, EFMC Yearbook 2003, pp. 14-28 (www.kubinyi.de)


+

Acetylcholine

CH3 O NCH3

CH3CH3

O OHN

ROH

OHEpinephrine, R = CH3Norepinephrine, R = H

N

OHNH2

Serotonin (5-HT)

NH2OH

OH Dopamine

Histamine

N

N

NH2 HH

H

Lead Structures: Endogenous Neurotransmitters


NH2 COOHGlycin

γγγγ-Aminobutyricacid (GABA)

Tyr-Gly-Gly-Phe-Met Tyr-Gly-Gly-Phe-Leu

NH2 COOH

Met-Enkephalin Leu-Enkephalin

OH

OH

H

HH

EstradiolO

H

HH

OCH3

Progesterone

Lead Structures: AAs, Peptides, Hormones


OHH H

H

OH

CH3

OH

OH

OH

p-Anol

Diethylstilbestrol

Estradiol

Serendipitous Discovery of Diethylstilbestrol


OH

H H

H

MeO

O

OH

H H

H

Mestranol

Norethynodrel (Searle)

1. Birch reduction

2. enol ether cleavage

The Serendipitous Discovery of the Pill


O

OH

OH

N CH3

HH

morphine

N

OH H N

CH

CH2

H

HMeO

quinine ephedrine

N

N N

NCH3

CH3

CH3

O

O

caffeine

colchicine

NHCOMe

OOMe

MeO

MeOMeO

OHN

CH3CH3

H

Lead Structures: Natural Products from Plants



Tubocurarin

- x 2 Cl

NMe Me OH

OH

O

NH Me

OMe

OOCH3

OHOH

O

OCH3

OH

O

OCH3

OH

O H

OH

R

OO

Digitoxin, R = HDigoxin, R = OH

MeO

+

+


N

H

COOCH3

O OCH3

cocaine

NH

O

O

OHCH3

N

atropine(racemate) coniine

NN

O

OOMe

OMeOMe

H

H

H

OMeO

MeO

MeO

H

H

reserpine

dicoumarol

(microbialdegradation product ofcoumarin)

O

OH

OO

OH

O



Jaques Louis David, The Last Hours of Socrates, MMA, New York


O

O OCH3

H

OH

CH3H

CH3HH

CH3NH2

NO

CH3

O

N OH

O

CH3

OH

OHOO

OO O

O O MeO

MeO

taxol

artemisinine

huperzine A

H

H



NH

NH O

O

O

OH

HH

OH

CH2OHH

OHH

H

H

OHH2N+

tetrodotoxin OHO

OH

H

ON CH3

CH3H O NH

O

CH3

CH3

batracho-toxin

compare: nicotine

epibatidine

N

NH

ClH

N

NCH3

H

Lead Structures: Natural Products from Animals


N

NHN

O

O

NN O

OH

H

H

asperlicin(CCK antagonist)

H

OH OH

OH

O OOH

CH3 N(CH3)2OH H

O

NH2

tetracyclin

streptomycin

OHOH

NHNH2

NHNH

NH2

NH

OHO

OCHO

CH3OHO

R1

OH

OH

R1 = -CH2OHR2 = -NHCH3R2

Lead Structures: Microbial Natural Products


COOHO

SCoenzym A

CH3

OHHMG-CoAreductase COOH

OH

CH3

OH

HMG-CoAmevalonic acid

cholesterol

compactin, R1 = H, R2 = Hlovastatin, R1 = Me, R2 = H

simvastatin, R1 = Me, R2 = Mepravastatin, R1 = OH, R2 = H; open lactone ring (sodium salt)

CH3CH3 R2

O

O H

O

OH O

CH3

R1

Ki = 150 nM

Lead Structures: Microbial Natural Products


atorvastatin(calcium salt)

N

ONH

FOH

OH

O

OH

OH

OOHOH

X

NYR

F

cerivastatin (sodium salt)X = C-CH2OMe, Y-R = CH-CH3

N

F

OH OH

OOH

fluvastatin(sodium salt)

Ki = 1.3 nMrosuvastatin (calcium salt)X = N, Y-R = N-SO2Me

Ki = 11 nM

Synthetic Statin Analogs


N

H

CH3H

NH

O

NH N

NO

CH3

OH

OH

OH ergotamine(Claviceps purpurea; ergot = Secale cornutum)

N

CO-N(Et)2

NH

NCH3H

H CO-N(Et)2

nicotinic acid

diethylamide LSD

Lead Structures: Other Natural ProductsAlbert Hofmann and His Problem Child LSD


J. L. Baryza, P. A. Wender et al., Chem. Biol. 11, 1261-1267 (2004);F. E. Koehn and G. T. Carter, Nature Rev. Drug Discov. 4, 206-220 (2005)

Simplification of a Natural Product

Recognition domain(pharmacophore)

Spacer domain

Ki = 1.35 nM Ki = 3 nMKi = 0.25 nM


N = natural products ND = derived from natural productsS = synthetic productsS* = synthetics but pharmacophore derived from natural productD. J. Newman et al., J. Nat. Prod. 66, 1022-1037 (2003)

All NCE‘s, 1981-2002, By Source(without biologicals and vaccines)

(n = 877)


All NCE‘s, 1981-2002, By Source

B = biologicals (usually peptides >45 aa) N = natural productsND = derived from natural products S = synthetic productsS/NM and S*/NM = synthetics but natural product mimicsS* = synthetics but pharmacophore derived from natural productV = vaccineD. J. Newman et al., J. Nat. Prod. 66, 1022-1037 (2003)

(n = 1031)


Diversity of Synthetics, Drugs and Natural Products

a) 13,506 compounds, randomly picked from CombiChem librariesb) natural products (n = 3,287)c) drugs (n = 10,968)

M. Feher and J. M. Schmidt, J. Chem.Inf. Comput. Sci. 43, 218-227 (2003)


Treatment of Parkinson‘s Disease

Parkinson‘s disease is caused by a degeneration ofdopamine-producing cells in certain brain areas

Approaches for drug treatmenta) anticholinergics: no causative therapy, side effectsb) dopamine substitution: dopamine is not bioavailable dopamine does not cross the blood-brain barrier systemic application of dopamine results in peripheral side effects dopamine action only very short

12


L-dopa

dopamine

dopa decarboxylase

dopaminetransporter

MAOinactivemetabolites

synaptic gap

presynapticnerve cell

postsynapticnerve cell

storagevesicals

postsynapticmembrane

presynapticmembrane

dopamine receptor with G-protein complex

ion channel

Ca2+

Ca2+

Interaction of Enzymes, Receptors, Ion Channels and Transportersin the Trans-mission of theElectric Signalof a Nerve Cell


A Rational Therapy of Parkinson‘s Disease

TherapyACh ! or dopamine "

Problemsdopamine is not bioavailable, peripheral side effects, MAO

oral L-DOPA,peripheral DOPAdecarboxylaseblocker, central MAO blocker

healthy sickACh + +dopamine + -


Integrated Optimisation of Drug Therapy Dopamine Substitution in Parkinson‘s Disease

OHOH

OH

NN

NH2

CH2OHO

NCH3

C CHCH3

benserazide (R)-(-)-selegiline

NH2OH

OH

NH2OH

OH COOH

dopamine L-dopa, a dopamine prodrug

H

H


New Strategies in Drug Design

Design of inhibitors from the structure of the substrate

Pharmacophore hypotheses and peptidomimetics

Structure-based design of ligands affinity, selectivity and drug resistance

Computer-aided design of ligands de novo design: LUDI, FlexX

Virtual screening for favourable drug properties drug character, bioavailability (rule of five)

Combinatorial design of ligands

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