pharmacophore analyses - university of wisconsin–eau claire pharmacognosy 491...(sadowski rules,...
TRANSCRIPT
Hugo Kubinyi, www.kubinyi.de
PharmacophoreAnalyses
Hugo Kubinyi
Germany
E-Mail [email protected] www.kubinyi.de
Hugo Kubinyi, 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)
=
Hugo Kubinyi, www.kubinyi.de
Diversity selections
Cluster-based methods
Dissimilarity-based methods
Cell-based methods
Stochastic methods
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
Pharmacophore Definitionsproperties: A, D, L (A, D, P, N, Ar, Al)distance bins
four-pointpharmacophore
three-pointpharmacophores
pharmacophore points
...
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
+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
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
CATALYST(Accelrys)
pharmaco-phorehypothesis of 5-HT3ligands for3D databasesearches
www.accelrys.com
Hugo Kubinyi, www.kubinyi.de
LigandScout (inte:ligand)
1dhfG. Wolber and T. Langer, J. Chem. Inf. Model. 45, 160-169 (2005)
Hugo Kubinyi, www.kubinyi.de
LigandScout (inte:ligand)
1dhfG. Wolber and T. Langer, J. Chem. Inf. Model. 45, 160-169 (2005)
Hugo Kubinyi, www.kubinyi.de
O
NH
COOHOH
OHOH
AcNH
NH2
NH
Zanamivir1nnc
LigandScout Superposition: Zanamivir vs. GS 4071
Hugo Kubinyi, www.kubinyi.de
O
NH2
COOH
AcNH
(Et)2HC
GS 4071 (active form of oseltamivir)
2qwk
LigandScout Superposition: Zanamivir vs. GS 4071
Hugo Kubinyi, www.kubinyi.de
LigandScout Superposition: Zanamivir vs. GS 4071
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
Hugo Kubinyi, www.kubinyi.de
1nnc
2qwk
LigandScout Superposition: Zanamivir vs. GS 4071
Hugo Kubinyi, www.kubinyi.de
LigandScout Superposition: Zanamivir vs. GS 4071
1nnc
2qwk
Hugo Kubinyi, www.kubinyi.de
LigandScout Superposition: Zanamivir vs. GS 4071
1nnc
2qwk
Hugo Kubinyi, www.kubinyi.de
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.)
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
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 configura- tions, 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 pharmaco- phores (option)
Pre-Processing of Compound Databases, II
Hugo Kubinyi, www.kubinyi.de
GarbageFilter
reactivefunctionalgroupswhich produce in vitro falsepositivescreeninghits
Hugo Kubinyi, www.kubinyi.de
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+
+
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
J. D. Watson and F. H. C. Crick, Nature 171, 737-738 (April 25, 1953)
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
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
** *
Hugo Kubinyi, www.kubinyi.de
Esters
Oxazoles
© http://ictsg10.unil.ch/ict/systahl/frag2/frag2_index.htm
?
Acceptor Potentials of Esters and Oxazoles
Hugo Kubinyi, www.kubinyi.de
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?
Hugo Kubinyi, www.kubinyi.de
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
+
Hugo Kubinyi, www.kubinyi.de
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)
Hugo Kubinyi, www.kubinyi.de
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.
Hugo Kubinyi, www.kubinyi.de
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
Hugo Kubinyi, www.kubinyi.de
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