Scaffold Hopping - OpenEye Scientific Software

Hugo Kubinyi, www.kubinyi.de
Hugo Kubinyi, www.kubinyi.de
A Prologue
to Ant and his friends
or: the problem with physics
The Dilemma of Computer-Aided Drug Design
The underlying physical laws necessary for
the mathematical theory of a large part of
physics and the whole of chemistry are thus
completely known, and the difficulty is only
that the exact application of these laws leads
to equations much too complicated to be
soluble.
P. A. M. Dirac, Proc. R. Soc. London 123, 714-733
(1929)

Hugo Kubinyi, www.kubinyi.de
Hugo Kubinyi, www.kubinyi.de
“Wolpertinger” Albrecht Dürer, (Bavaria, “Young Hare” Germany)
(1502)
Fifth Solvay Congress, Brussels (1927)
Scaffold Hopping -
A Successful
Design Strategy
Hugo Kubinyi
Germany
E-Mail kubinyi@t-online.de
URL www.kubinyi.de

Hugo Kubinyi, www.kubinyi.de
Overview
Medicinal chemists always used scaffold hops
Oldies but goodies: the program CAVEAT
Straightforward design of peptidomimetics
Scaffold hops by fragment similarity
Don’t forget the pharmacophore
Surprises - scaffold hops may result in binding hops
Scaffold hops are a perfect modification strategy
Many blockbuster drugs resulted from scaffold hops
BROOD - comparison of scaffold MEPs
ReCore - a versatile scaffold hopping program
Conclusions
Hugo Kubinyi, www.kubinyi.de
Classical Scaffold Hops: Receptor Ligands
HO
Me
HN
N
H
H H
Estradiol
S
OH
H
N
H
N
N CN
Me
N
Me
Me
HO
O
Diethylstilbestrol
Cimetidine
S
Ranitidine
H
N
HC
H
N
OH
NO 2
Me

Hugo Kubinyi, www.kubinyi.de
Cl
Cl
Classical Scaffold Hops: Receptor Ligands
HO
HO
OH
H
N
N
H
CH 3
CH 3
R
N
H
R
O
OH
Dichloroisoprenaline Propranolol
R
R
N
R
S
O
N
R
O
N
N S
H
N
CH 3
N
H
CH 3
Indenolol Pindolol Carazolol Carteolol
Nadolol Tazolol Timolol
Hugo Kubinyi, www.kubinyi.de
Cl
O
N
H
N
N(Me) 2
N
N
Me
N
S
N
H
N
N
N(Me) 2
S
N
Me
olanzapine
(atypical neuroleptic)
Cl N
Me
N
S
N
R
and many
others ...
Classical Scaffold Hops: Receptor Ligands
diphenhydramine
(H 1 antagonist)
clozapine
(atypical neuroleptic)
chlorpromazine
(neuroleptic)
N(Me) 2
imipramine
(antidepressant)
N
(CH 2 ) 2 O(CH 2 ) 2 OH
quetiapine
(atypical neuroleptic)

Hugo Kubinyi, www.kubinyi.de
Even Nature Uses Scaffold Hops: Antibiotics
RHN
O
H
N
Penicillins
Hugo Kubinyi, www.kubinyi.de
NH
O
N
H
HN
S
H NH
N
HN
O
O
Me
Me
COOH
NH 2
OH
RHN
O
H
N
S
COOH
CH 2 OH
Cephalosporins
H
O OH
N
O
COOH
Clavulanic acid
OMe
H RHN
RHN
N
O
N
SO3H O SO3H Monobactams
CAVEAT for the Design of Peptidomimetics
attach and modify
the side chains
extract
vectors
A
B
C
search for
appropriate
scaffold
G. Lauri and P. A. Bartlett, J. Comput.-Aided Mol. Design 8, 51-66 (1994)

Hugo Kubinyi, www.kubinyi.de
HN
N
H 2
Rational Design of Integrin Ligands
N
H
v
O
NH
H
N
O
F
HN
NH O
O NH
R G D
Hugo Kubinyi, www.kubinyi.de
O
O
COOH
cyclo(RGDFv)
(v = D-Valine)
N
H 2
N
H 2
NH
NH
H
N
C
H 3
H
N
S S
N O
H
N
O
HN
O
N
H
O
COOH
O
K i = 2.0 nM
N
H
N
O
COOH
K i = 2.3 nM
Design of an Orally Active TRH Mimetic
NH
O
N
H
TRH
H
N
N
N
O CONH 2
metabolically not stable,
no oral bioavailability
H
N
N
O
Ph
N
CONH2 peptidomimetic,
orally bioavailable,
sufficient half-life time
G. L. Olson et al., J. Med. Chem. 36, 3039-3049 (1993)

Hugo Kubinyi, www.kubinyi.de
NH 2
Scaffold Hops to Somatostatin Mimics
O
O
O
3-deoxyglucose
O
O
NH
mimic of the receptor-recognizing
ß-turn Phe7-Trp8-Lys9-Thr10 of
somatostatin; agonist activity at 3 µM
K. C. Nicolaou et al., Peptide Chem.
Struct. Biol., Proceedings of the 11th
Am. Peptide Symp., 1990, pp. 881-884
Hugo Kubinyi, www.kubinyi.de
S
O O
NH 2
O
O
O
O
glucose
O R
O
NH
R = phenyl: non-selective, weak
sst-receptor partial agonist
R = imidazol-4-yl: selective
sst4-receptor agonist, 100 nM
R. Hirschmann et al., J. Med.
Chem. 41, 1382-1391 (1998)
TOPAS (TOPology-Assigning System)
HO
H
N
H
N
O
template
Ki hK channel 1.5 = 0.11 µM
OMe
R
S
O O
designed analog
(R = OMe)
NH
H
N
OMe
R = OMe: Ki hK channel 1.5 = 7.34 µM
R = H: Ki hK channel 1.5 = 0.47 µM
Scaffolds and building blocks from a RECAP process
are re-assembled by their 3D similarity to the template
(„fragment-based evolutionary design“).
G. Schneider et al., Angew. Chem. Int. Ed. Engl. 39, 4130-4133 (2000)

Hugo Kubinyi, www.kubinyi.de
O
A Binding Site Recognizes Pharmacophores,
not Atoms: Scytalone Dehydratase Inhibitors
H
N
H
O
His133
Asn131
H
O
N
R
Salicylamide
H
H
H
O
R = -CH(CH 3 )C 6 H 4 -p-Br
K i = 0.14 nM
Trp26
HO-Tyr30
HO-Tyr50
O H
H His110
His85
H
N
H
J. M. Chen et al., Biochemistry 37, 17735-17744 (1998)
Hugo Kubinyi, www.kubinyi.de
MeO
OH
OMe
O
OMe
MeO
O
Asn131
N
Quinazoline
His133
N
N H
R
H
H
O
R = -CH 2 CH 2 CH(C 6 H 5 ) 2
K i = 0.15 nM
OMe
N N
MeO
Trp26
HO-Tyr30
HO-Tyr50
O H
H His110
His85
Bioisosterism of Salicylates and Quinazolines
SDZ LAP 977 SDZ LAV 694
IC 50 =
OMe
N N
47 nM 7 nM 4 nM
(inhibition of tubulin polymerisation; antiproliferative
activity in a keratinocyte cell line)
P. Nussbaumer, Novartis, 17th Int. Symp. Med. Chem., Sept. 2002
O

Hugo Kubinyi, www.kubinyi.de
Scaffold Hops Should Consider Pharmacophores
(corticotropin-releasing factor-1 (CRF1) receptor antagonists)
N
N
N
N NH
Me Me
Me
N
N
N NH
Cl Cl
Cl
N
N
N NH
Cl Cl
Cl
N
N
N NH
Cl Cl
Cl
N
N N
NH
Cl Cl
Ki CRF1 =
57 nM 70 nM 30 nM 2 nM >10,000 nM
C. Chen et al., J. Med. Chem. 39, 4358-4360 (1996)
Hugo Kubinyi, www.kubinyi.de
Scaffold Hops Should Consider Pharmacophores
(binding modes of COX2 inhibitors
to carbonic anhydrase)
N
N
SO 2 NH 2
F 3 C SO2 NH 2
Me
O N
Celecoxib
(blue)
Valdecoxib (red)
Me
A. Di Fiore et al., Bioorg. Med. Chem. Lett. 16, 437-442 (2006)
Cl
(1oq5, 2aw1)

Hugo Kubinyi, www.kubinyi.de
N
NH N NH
N N
1-Phenyl4-Phenyl2-Phenylimidazoleimidazoleimidazole 1.0 . 10 -7 M 4.0 . 10 -5 M 7.0 . 10 -6 M
Hugo Kubinyi, www.kubinyi.de
Me
O
HN
N
O S
NH-tBu
O
Me
O
O S
N
O
Scaffold Hops to „me too“ Analogs
HN
O
N
N
H
N
N
N
early lead structure
(different indication)
O Me
N Et
N
Me
Me
Me
O
O S
N
O
O
HN
HN
O
N
O Me
N
N
N
N Me
N
Me
Me
Sildenafil
Vardenafil Mirodenafil
O S
N
O
Me
N
CH2CH OH 2

Hugo Kubinyi, www.kubinyi.de
Scaffold Hops to Chemically Stable Fungicides
Me
O
OMe
Me
O OMe
strobilurin A
(potent fungicide, unstable)
O
N
OMe
OMe
kresoxim methyl
(BASF)
Hugo Kubinyi, www.kubinyi.de
C
H 3
MeO
C
H 3
Me
O
F
N
HO O
O H
O
CH 3
CN
O
N
O OMe
OMe
first lead structure
(chemically stable)
N
azoxystrobin
(ICI / Zeneca)
A Huge Hop to a Blockbuster
Lovastatin
OH
OH
O
F
OH
Cerivastatin
(withdrawn)
N
Fluvastatin
OH OH
F
O NH
O
O OMe
N
O
OMe
OH
OH
OH
O
Atorvastatin
OH

Hugo Kubinyi, www.kubinyi.de
Thr-106
R. Buijsman, in H. Kubinyi
and G. Müller, Chemogenomics
in Drug Discovery, Wiley-VCH,
2004, pp. 191-219
Hugo Kubinyi, www.kubinyi.de
O
Met-109
O
HN
N
Gly-110
His-107
Software for Scaffold Hopping
N
O
H
Kinase Inhibitors:
Various Scaffold
Hops to Mimic ATP
H
H
O
Cl
Thr-106
CAVEAT (Paul Bartlett)
CATS and TOPAS (Gisbert Schneider, Roche)
Skelgen (Phil Dean, Roche)
Shop (Ismael Zamora)
FieldStere (Cresset)
BROOD (OpenEye)
ReCore
(Matthias Rarey,
BioSolveIT)
N
N
N
Cl
F
N
BR-II
BR-I
F
NH
Asp-168
PBR

Hugo Kubinyi, www.kubinyi.de
Conclusions
Scaffold hops are a well-established strategy in lead structure
optimization
Scaffold hops offer new opportunities and chances
- enhancement of biological activity
- modulation of selectivity
- modulation of physicochemical properties
- intellectual property of „me too“ analogs
Cave: modification of the pharmacophore may change the
binding mode
Software should stimulate your creativity
“whenever people turn on the computer, they are tempted to
switch off their brain at the same time, relying too much on
some intelligence within the (commercial) programs”
quoted from Nature Rev. Drug. Discov. 2, 665-668 (2003)
Hugo Kubinyi, www.kubinyi.de
Selected References
G. Lauri and P. A. Bartlett, CAVEAT: A program to facilitate the design
of organic molecules, J. Comput.-Aided Mol. Design 8, 51-66 (1994).
G. Schneider, W. Neidhart, T. Giller and G. Schmid, "Scaffold-hopping"
by topological pharmacophore search: a contribution to virtual
screening, Angew. Chem. Int. Ed. Engl. 38, 2894-2896 (1999).
D. G. Lloyd, C. L. Buenemann, N. P. Todorov, D. T. Manallack and
P. M. Dean, Scaffold hopping in de novo design. Ligand generation in
the absence of receptor information, J. Med. Chem. 47, 493-496 (2004).
S. Renner and G. Schneider, Scaffold-hopping potential of ligand-based
similarity concepts, ChemMedChem 1, 181-185 (2006).
P. Maass, T. Schulz-Gasch, M. Stahl and M. Rarey, Recore: a fast and
versatile method for scaffold hopping based on small molecule
crystal structure conformations, J. Chem. Inf. Model. 47, 390-399 (2007).