pharmacophore analyses - kubinyi · hugo kubinyi, pharmacophore analyses hugo kubinyi germany...

Hugo Kubinyi, www.kubinyi.de

PharmacophoreAnalyses

Hugo Kubinyi

Germany

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


Similarity and Dissimilarity2D similarity based on groups + connectivity

e.g., Daylight fingerprints or MDL keys

2D similarity = Tanimoto index

0 <= Tanimoto Index (i, j) <= 1

e.g. (example): T(A,B) = 5 / 9 = 0.555

# bits set in A and B

# bits set in A or B=

2D dissimilarity = 1 - Tanimoto Index

A AA B and or B B

NAB

NA + NB - NAB

# keys common in A and B

(# keys in A) (# keys in B) - (# keys common in A and B)

=


Diversity selections

Cluster-based methods

Dissimilarity-based methods

Cell-based methods

Stochastic methods


x1x2

xN

w1w2

wN

Self-organizing Maps (SOM, Kohonen Maps; (© J. Gasteiger)

Competitive layer

Object with N (=49)

input data

N weights

Step 1: initialization of weights with random valuesStep 2: comparison of weights with all inputdata vectorsStep 3: most similar weight vector is associated with inputvector which influencesits neighborhood withina given radius

Loop many times with decreasing neighbour-hood radius until chart stabilizes


112 dopamine and 60 benzodiazepine agonists in a much larger set of 8323 structures of unknown biological activity

Self-organizing Maps (SOM, Kohonen Maps)Classification of large datasets (© J. Gasteiger)


Pharmacophore (pharmacophoric pattern)A pharmacophore is the ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response.A pharmacophore does not represent a real molecule or a real association of functional groups, but a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds towards their target structure. The pharmacophore can be considered as the largest common denominator shared by a set of active molecules. This definition discards a misuse often found in the medicinal chemistry literature which consists of naming as pharmacophores simple chemical functionalities such as guanidines, sulfonamides or dihydroimidazoles (formerly imidazolines), or typical structural skeletons such as flavones, phenothiazines, prostaglandins or steroids.Pharmacophoric descriptors are used to define a pharmacophore, including H-bonding, hydrophobic and electrostatic interaction sites, defined by atoms, ring centers and virtual points.C. G. Wermuth et al., Pure Appl. Chem. 70,1129-1 143 (1998)


Pharmacophore Definitionsproperties: A, D, L (A, D, P, N, Ar, Al)distance bins

four-pointpharmacophore

three-pointpharmacophores

pharmacophore points

...


Pharmacophore Hypotheses - ACE Inhibitors

NNN

O

O COOH

SH

NN

O

O COOH

SH

NN

O

O COOH

SH

NO

CH3SH

COOH

SN

O

SH

COOH

OH

NO

CH3

NP

COOH

OH

OH

O

NO

CH3SH

COOH

NO

CH3SH

COOH

O

O COOH

NSH

NO COOHSH

NO COOHSH

NO COOH

CH3

N

O

SH

NO

CH3

NCOOH

HOOC

ON

COOH

NHOOCNO

P

COOHOHO

SS

ON

COOH

NCH3HOOC

NNN

O

O COOH

HOOC

S

COOHN

O

OH

HOOC

S

ON

COOH

NHOOC

H

H

HH H

H H

POH

O

N

O

CH3

NCOOH

H


+N

NH

NH3 +N

NH

NH3+ H

D

A P3 P

P

P3

+N

N

NH3

H

D

A

P3

+NH

N NH3+

NHNH NH3+

+N

NH NH3

Pharmacophores

D

A

P3

D

A P3 P

P

P3

Pharmacophores

Pharmacophore Hypotheses - Histamine


NH3OH

OH

+

LPDD/A

D/A

NH

OHOH

CH3H +

ττττ1 ττττ2

NH3

OHOH

+NH3

OH

OH +

NH

NHH CH3

H COOH

+NH3

OHOH

+

LPD

D

d1

57

d2d3

d1

d2

d3

Pharmacophore Hypotheses - Dopamine


Pharmacophore Hypothesis for 5-HT1A Ligands

M. F. Hibert et al., J. Med. Chem. 31, 1087-1093 (1988)

S

N

NMe

SMeN

O

F

NH

O

NN

ONN

N

O

OOH

NH

methiothepin

spiperone

buspironepropranolol

proposed molecule: pIC50 = 9.1(25x more active than mostactive analog in the training set:buspirone, pIC50 = 7.7)

O

O

HNH

N

O

O

MDL-72832

training set for pharmacophorehypothesis


COOH9-11 Å

O

O

COOH

O

OCOOH

O

OCN

COOH

Lead structureIC50 = 750 nM

Lead structureIC50 = 9,000 nM

optimizedstructureIC50 = 5 nM

Pharmacophore Hypotheses forETA-Receptor Antagonists

P. C. Astles et al., Eur. J. Med. Chem. 32, 409-423 (1997)


A Unique Pharmacophore Hypotheses forETA-Receptor Antagonists

O

O

S

O

O

O

O

NNH

OO-

-

pharmacophore hypotheses

P. C. Astles, J. Med. Chem. 41, 2732-2744 (1998)

O

O

S

O

O

O

O

NNH

OO -

-

cationic siteon receptor?

superposition


CATALYST(Accelrys)

pharmaco-phorehypothesis of 5-HT3ligands for3D databasesearches

www.accelrys.com


LigandScout (inte:ligand)

1dhfG. Wolber and T. Langer, J. Chem. Inf. Model. 45, 160-169 (2005)


LigandScout (inte:ligand)

1dhfG. Wolber and T. Langer, J. Chem. Inf. Model. 45, 160-169 (2005)


O

NH

COOHOH

OHOH

AcNH

NH2

NH

Zanamivir1nnc

LigandScout Superposition: Zanamivir vs. GS 4071


O

NH2

COOH

AcNH

(Et)2HC

GS 4071 (active form of oseltamivir)

2qwk




graphics: LigandScout(inte:ligand, Innsbruck)

1nnc

2qwk

}the images of the binding sites areturned around by180° to show thedifferences in theglycerol- vs. alkyl-binding pockets


1nnc

2qwk




1nnc

2qwk



1nnc

2qwk


Problems in Pharmacophore Definition

Ionisation and Dissoziation (Sadowski rules, ACS Boston, 2002)

Tautomeric and protomeric forms (program AGENT, ETH Zurich; ChemoSoft tautomer recognition, ChemDiv)

Acceptor properties of oxygen and sulfur atoms (esters, aromatic ethers, oxazoles, isoxazoles, thiazoles, etc.)


Pre-Processing of Compound Databases, I

Removal of duplicatesElimination of counterions Garbage filter: chemically reactive groups (e.g. electrophiles, metal chelators, Michael acceptors), undesirable atoms (e.g. organo- metallic complexes); certain groups (option)Dissociation / protonation equilibria of acids and basesProtomeric equilibria (e.g. imidazole)Tautomeric equilibria (or predominant tautomers)


Property filters, e.g. MW, lipophilicity, solubility, PSA, ... (option)Bioavailability filters, e.g. Lipinski ROF (option)Lead-like / drug-like character (option)Selection by chemical diversity (option)Generation of correct or alternative configurations, enantiomers, diastereomers Generation of „reliable“ 3D structures, by e.g. CORINA, CONCORD, and/or multiple 3D structures, by CATALYST, Mimumba (option)Definition or elimination of certain pharmacophores (option)

Pre-Processing of Compound Databases, II


GarbageFilter

reactivefunctionalgroupswhich produce in vitro falsepositivescreeninghits


The Importance of Correct Conformations

CH3 N

OCH3

HCH3 N

O

CH3

H

cis (about 3%) trans (about 97%)

CH3 O

OCH3CH3 O

O

CH3

cis (< 0.01%) trans (> 99.99%)

acyclic amides acyclic esters

very slow interconversion (<1 sec-1) no interconversion

amines

R1N

R2R3 R1

N

R2R3

protonated amines

R1N

R2R3 R1

N

R2R3

equilibrium, rapid interconversion two different configurations(enantiomers)

H

H+

+


Dissociation of Acids and Protonation of Basesstrong acids CF3COOHacids arom. + aliph. COOH, CF3SO2NH2, tetrazoleweak acids arom. OH, arom. SO2NH2neutral aliph. -OH, -CONH2weak bases arom. NH2, imidazolebases aliph. NH2strong bases amidines, guanidines

NH

NN

NHN

NNH

NN

NHN

NHN N

NHneutral pKa = 2.48 pKa = 6.99

pKa = 1.15 pKa = 2.45 pKa = 4.90

J. Catalan et al., Adv. Heterocyclic Chem. 41, 187-274 (1987)

pKa Values of Selected Organic Compounds


Dissociation of Acids and Protonation of Bases

Sadowski (AstraZeneca) rules(ACS Meeting August 2002, Boston)

permanently charged: acids, amidines, guanidines, quart. N, ...

negative charges: tetrazole, thiols, hydroxamic acids, acidic nitrogen (e.g. activated sulfonamides), ...

positive charges: basic amines, imidazoles, pyridines, ...

protonation restrictionsmaximum number of permanent charges per molecule maximum number of „chargable“ atoms maximum total charge maximum number of charges in the same ringno identical charges in adjacent positions


Gln 92

Thr 199

HN

OH

SOO

NH

CH3

CH3S

SO

ON

H

HN

HO

Zn2+

-

Dorzolamide,anion Ki = 0.37 nM

N N

Me

SO2NH2

F3C

O

SO2CH3

O Rofecoxibno inhibition(withdrawn inOctober 2004)

Celecoxib Ki = 21 nM (hCA II)

Dissociation of Carbonic Anhydrase Inhibitors

A. Weber et al., J. Med. Chem. 47, 550-557 (2004)


NN

O

O

n-Butyl

Phe

Phe

H

Phenyl-butazonepKa = 4.5

Diphenyl-hydantoinpKa = 8.3

O

N

NPheEt

O

O O

CH3N-Methyl-phenobarbitalpKa = 7.4

H

NH

NPhe

PheO

H

N

NPheEt

O

O O

CH3

-

O

N

NPhe

PheO

HO

NH

NPhe

PheO

-

-

NN

O

O

n-Butyl

Phe

Phe- ?

Dissociation of Selected Organic Compounds


Some Typical Tautomeric EquilibriaO O

NH

ON OH

OH O O OH

NH

NR

N

NHRbut:

OH

OR

O

N

OHCOOH

NH

OCOOH

N

NOH

OH

NH

NH

O

O

O

OR

O

NH

NHMeO

SN

NHMeO

SH

ACD # 126 388Maybridge RH 00232

ACD # 40 405Maybridge KM 07202


adenine thymine

N

H

N

NN

NH

H

guanine cytosine

N

NN

N

NH

OH

H

H

N

N

NH

O

HH OH

N

NH

Me

O

The Discovery of the DNA Double Helix

J. N. Davidson, The Biochemistry of Nucleic Acids, London, 1950

early 1953: Pauling publishes a DNA model with a phosphate coreFebruary 27, 1953: Jerry Donohue corrects the formulas of the basesFebruary 28, 1953: Watson and Crick derive the correct DNA modelApril 02, 1953: Manuscript sent to Nature; published April 25, 1953

cited from: J. Watson and A. Berry, DNA. The Secret of Life, 2003

Summer 1952: Erwin Chargaff critisizes that Francis Crick and James Watson are ignorant about the structures of the bases


J. D. Watson and F. H. C. Crick, Nature 171, 737-738 (April 25, 1953)


bases: adenine thymine

N H

H O

N

NN

NRibose

H

NN

Me

O Ribose

bases: guanine cytosine

NN

N

N

NRibose

O

H

HH

N

NN

O Ribose

HH

A-T andG-C Pairs in DNA

(Watson andCrick, 1953)


O

OH

O

O

O

OH

O

warfarin(screeningat Upjohn)IC50 = 30 µM

phenprocoumon(similarity searchat Upjohn)IC50 = 1 µM

O

OH

O

O

screening atParke/Davis Ki = 2.3 µM

HIV-Protease Inhibitors from Anticoagulants

tipranavir (PNU 140 690)

OONH NSO O

OH

CF3

6

3a

diastereo- Ki IC50 IC90 mer pM µM µMR,R 8 0.03 0.10

R,S 18 0.14 0.84

S,R 32 0.41 1.8

S,S 220 1.7 3.0

S. R. Turner et al., J. Med. Chem. 41, 3467-3476 (1998)


Tautomeric Forms of an MMP-8 Inhibitor (1jj9)

N

H

O

NH

O O

HO

N

NH

O

N

O

N

O

Leu160Glu 198

Zn2+

-Ala161

OO O

HO N

H

OR

Glu 198

Zn2+

-Ala161

Ro 200-1770

Batimastat

H. Brandstetter et al., J. Biol.Chem. 276, 17405-17412 (2001)

NHNH

O

O

O

R1R2

NHN

O

OH

O

R1R2

NNH

O

OH

O

R1R2

"enantiomer I" prochiral "enantiomer II" form

** *


Esters

Oxazoles

© http://ictsg10.unil.ch/ict/systahl/frag2/frag2_index.htm

?

Acceptor Potentials of Esters and Oxazoles


Pharmacophore Analyses Must Consider CorrectDonor and Acceptor Properties of LigandsThe billion dollar question: how many acceptor positions has an ester group ?Correct answer: Two ...., but why?


Donor and Acceptor Properties of O and N

OH aliph

Oaliph arom

Oaliph arom

Oarom

OO

O

NH

O

NH

N

N

NH

NH

NH

+


Acceptor Properties of O, N and S

N

O

S

NN

SN

ON

SN

NO

N

NO

N

23

1 322

5

22

254

54

3

91 29 2

oxazole isoxazole

thiazole isothiazole 1,3,4-thiadiazole

1,2,4-oxadiazole 1,2,5-oxadiazole

hydrogen bonding contacts observed in the Cambridge Crystallo-graphic Database are indicated as red numbers (www.ccdc.cam.ac.uk/prods/isostar/appnot1.html)

a) isoxazole thiazole

b)


References: Acceptor Properties of O and NP. Murray-Rust, J. P. Glusker, Directional hydrogen bonding to sp2- and sp3-hybridized oxygen atoms and its relevance to ligand-macro-molecule interactions, J. Am. Chem. Soc. 106, 1018-1025 (1984).H.-J. Böhm, S. Brode, U. Hesse, G. Klebe, Oxygen and nitrogen in competitive situations: Which is the hydrogen-bond acceptor? Chem. Eur. J. 2, 1509-1513 (1996).I. J. Bruno, J. C. Cole, J. P. M. Lommerse, R. S. Rowland, R. Taylor, M. L. Verdonk, IsoStar: A library of information about nonbonded interactions, J. Comput.-Aided Mol. Design 11, 525-37 (1997).J. P. M. Lommerse, S. L. Price, R. Taylor, Hydrogen bondingof carbonyl, ether, and ester oxygen atoms with alkanolhydroxyl groups, J. Comput. Chem. 18, 757-774 (1997)R. Taylor, Life-science applications of the Cambridge StructuralDatabase, Acta Cryst. D58, 879-888 (2002).Isostar (CCDC): www.ccdc.cam.ac.uk/prods/isostar/index.html.


Scytalone Dehydratase Inhibitors

HO-Tyr30

HO-Tyr50

NH

H

O

OO

NR

H

HO H

H

OH

H

Asn131

His110

His85

His133Trp26

Salicylamide

R = -CH(CH3)C6H4-p-Br

Ki = 0.14 nM

J. M. Chen et al., Biochemistry 37, 17735-17744 (1998)

NN

NR

OH

H

H

Asn131

Quinazoline

R = -CH2CH2CH(C6H5)2

Ki = 0.15 nM


MeO

OMe

N N

MeO

OH

OMe

O

OMe

MeO

OMe

N N

O

47 nM 7 nM 4 nM

SDZ LAP 977 SDZ LAV 694

IC50 =

(inhibition of tubulin polymerisation; antiproliferative activity in a keratinocyte cell line)

Bioisosterism of Salicylates and Quinazolines

P. Nussbaumer, Novartis, 17th Int. Symp. Med. Chem., Sept. 2002

pharmacophore analyses - kubinyi · hugo kubinyi, pharmacophore analyses hugo kubinyi germany...

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