Scaffold Hopping - OpenEye Scientific Software
Scaffold Hopping - OpenEye Scientific Software
Scaffold Hopping - OpenEye Scientific Software
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Hugo Kubinyi, www.kubinyi.de<br />
Hugo Kubinyi, www.kubinyi.de<br />
A Prologue<br />
to Ant and his friends<br />
or: the problem with physics<br />
The Dilemma of Computer-Aided Drug Design<br />
The underlying physical laws necessary for<br />
the mathematical theory of a large part of<br />
physics and the whole of chemistry are thus<br />
completely known, and the difficulty is only<br />
that the exact application of these laws leads<br />
to equations much too complicated to be<br />
soluble.<br />
P. A. M. Dirac, Proc. R. Soc. London 123, 714-733<br />
(1929)
Hugo Kubinyi, www.kubinyi.de<br />
Hugo Kubinyi, www.kubinyi.de<br />
“Wolpertinger” Albrecht Dürer, (Bavaria, “Young Hare” Germany)<br />
(1502)<br />
Fifth Solvay Congress, Brussels (1927)<br />
<strong>Scaffold</strong> <strong>Hopping</strong> -<br />
A Successful<br />
Design Strategy<br />
Hugo Kubinyi<br />
Germany<br />
E-Mail kubinyi@t-online.de<br />
URL www.kubinyi.de
Hugo Kubinyi, www.kubinyi.de<br />
Overview<br />
Medicinal chemists always used scaffold hops<br />
Oldies but goodies: the program CAVEAT<br />
Straightforward design of peptidomimetics<br />
<strong>Scaffold</strong> hops by fragment similarity<br />
Don’t forget the pharmacophore<br />
Surprises - scaffold hops may result in binding hops<br />
<strong>Scaffold</strong> hops are a perfect modification strategy<br />
Many blockbuster drugs resulted from scaffold hops<br />
BROOD - comparison of scaffold MEPs<br />
ReCore - a versatile scaffold hopping program<br />
Conclusions<br />
Hugo Kubinyi, www.kubinyi.de<br />
Classical <strong>Scaffold</strong> Hops: Receptor Ligands<br />
<br />
HO<br />
Me<br />
HN<br />
N<br />
H<br />
H H<br />
Estradiol<br />
<br />
S<br />
<br />
<br />
OH<br />
H<br />
N<br />
H<br />
N<br />
N CN<br />
Me<br />
N<br />
Me<br />
Me<br />
HO<br />
O<br />
Diethylstilbestrol<br />
Cimetidine<br />
S<br />
Ranitidine<br />
H<br />
N<br />
HC<br />
H<br />
N<br />
OH<br />
NO 2<br />
Me
Hugo Kubinyi, www.kubinyi.de<br />
Cl<br />
Cl<br />
Classical <strong>Scaffold</strong> Hops: Receptor Ligands<br />
HO<br />
HO<br />
<br />
OH<br />
H<br />
N<br />
N<br />
H<br />
CH 3<br />
CH 3<br />
R<br />
N<br />
H<br />
R<br />
O<br />
OH<br />
Dichloroisoprenaline Propranolol<br />
R<br />
R<br />
N<br />
R<br />
S<br />
O<br />
N<br />
R<br />
O<br />
N<br />
N S<br />
H<br />
N<br />
CH 3<br />
N<br />
H<br />
CH 3<br />
Indenolol Pindolol Carazolol Carteolol<br />
Nadolol Tazolol Timolol<br />
Hugo Kubinyi, www.kubinyi.de<br />
Cl<br />
O<br />
N<br />
H<br />
N<br />
N(Me) 2<br />
N<br />
N<br />
Me<br />
N<br />
S<br />
N<br />
H<br />
N<br />
N<br />
N(Me) 2<br />
S<br />
N<br />
Me<br />
olanzapine<br />
(atypical neuroleptic)<br />
<br />
Cl N<br />
Me<br />
N<br />
S<br />
N<br />
R<br />
and many<br />
others ...<br />
Classical <strong>Scaffold</strong> Hops: Receptor Ligands<br />
<br />
diphenhydramine<br />
(H 1 antagonist)<br />
clozapine<br />
(atypical neuroleptic)<br />
chlorpromazine<br />
(neuroleptic)<br />
N(Me) 2<br />
imipramine<br />
(antidepressant)<br />
N<br />
(CH 2 ) 2 O(CH 2 ) 2 OH<br />
quetiapine<br />
(atypical neuroleptic)
Hugo Kubinyi, www.kubinyi.de<br />
Even Nature Uses <strong>Scaffold</strong> Hops: Antibiotics<br />
RHN<br />
O<br />
H<br />
N<br />
Penicillins<br />
Hugo Kubinyi, www.kubinyi.de<br />
NH<br />
O<br />
N<br />
H<br />
HN<br />
S<br />
H NH<br />
N<br />
HN<br />
O<br />
O<br />
Me<br />
Me<br />
COOH<br />
NH 2<br />
OH<br />
RHN<br />
O<br />
H<br />
N<br />
S<br />
COOH<br />
CH 2 OH<br />
Cephalosporins<br />
H<br />
O OH<br />
N<br />
O<br />
COOH<br />
Clavulanic acid<br />
OMe<br />
H RHN<br />
RHN<br />
N<br />
O<br />
N<br />
SO3H O SO3H Monobactams<br />
CAVEAT for the Design of Peptidomimetics<br />
attach and modify<br />
the side chains<br />
extract<br />
vectors<br />
A<br />
B<br />
C<br />
search for<br />
appropriate<br />
scaffold<br />
G. Lauri and P. A. Bartlett, J. Comput.-Aided Mol. Design 8, 51-66 (1994)
Hugo Kubinyi, www.kubinyi.de<br />
HN<br />
N<br />
H 2<br />
Rational Design of Integrin Ligands<br />
N<br />
H<br />
v<br />
O<br />
NH<br />
H<br />
N<br />
O<br />
F<br />
HN<br />
NH O<br />
O NH<br />
R G D<br />
Hugo Kubinyi, www.kubinyi.de<br />
O<br />
O<br />
COOH<br />
cyclo(RGDFv)<br />
(v = D-Valine)<br />
N<br />
H 2<br />
N<br />
H 2<br />
NH<br />
NH<br />
H<br />
N<br />
C<br />
H 3<br />
H<br />
N<br />
S S<br />
N O<br />
H<br />
N<br />
O<br />
HN<br />
O<br />
N<br />
H<br />
O<br />
COOH<br />
O<br />
K i = 2.0 nM<br />
N<br />
H<br />
N<br />
O<br />
COOH<br />
K i = 2.3 nM<br />
Design of an Orally Active TRH Mimetic<br />
NH<br />
O<br />
N<br />
H<br />
<br />
TRH<br />
H<br />
N<br />
N<br />
N<br />
<br />
O CONH 2<br />
metabolically not stable,<br />
no oral bioavailability<br />
H<br />
N<br />
N<br />
O<br />
Ph<br />
N<br />
CONH2 peptidomimetic,<br />
orally bioavailable,<br />
sufficient half-life time<br />
G. L. Olson et al., J. Med. Chem. 36, 3039-3049 (1993)
Hugo Kubinyi, www.kubinyi.de<br />
NH 2<br />
<strong>Scaffold</strong> Hops to Somatostatin Mimics<br />
O<br />
O<br />
O<br />
3-deoxyglucose<br />
O<br />
O<br />
NH<br />
mimic of the receptor-recognizing<br />
ß-turn Phe7-Trp8-Lys9-Thr10 of<br />
somatostatin; agonist activity at 3 µM<br />
K. C. Nicolaou et al., Peptide Chem.<br />
Struct. Biol., Proceedings of the 11th<br />
Am. Peptide Symp., 1990, pp. 881-884<br />
Hugo Kubinyi, www.kubinyi.de<br />
S<br />
O O<br />
NH 2<br />
O<br />
O<br />
O<br />
O<br />
glucose<br />
O R<br />
O<br />
NH<br />
R = phenyl: non-selective, weak<br />
sst-receptor partial agonist<br />
R = imidazol-4-yl: selective<br />
sst4-receptor agonist, 100 nM<br />
R. Hirschmann et al., J. Med.<br />
Chem. 41, 1382-1391 (1998)<br />
TOPAS (TOPology-Assigning System)<br />
HO<br />
<br />
H<br />
N<br />
<br />
H<br />
N<br />
O<br />
template<br />
Ki hK channel 1.5 = 0.11 µM<br />
OMe<br />
R<br />
S<br />
O O<br />
designed analog<br />
(R = OMe)<br />
NH<br />
H<br />
N<br />
OMe<br />
R = OMe: Ki hK channel 1.5 = 7.34 µM<br />
R = H: Ki hK channel 1.5 = 0.47 µM<br />
<strong>Scaffold</strong>s and building blocks from a RECAP process<br />
are re-assembled by their 3D similarity to the template<br />
(„fragment-based evolutionary design“).<br />
G. Schneider et al., Angew. Chem. Int. Ed. Engl. 39, 4130-4133 (2000)
Hugo Kubinyi, www.kubinyi.de<br />
O<br />
A Binding Site Recognizes Pharmacophores,<br />
not Atoms: Scytalone Dehydratase Inhibitors<br />
H<br />
N<br />
H<br />
O<br />
His133<br />
Asn131<br />
H<br />
<br />
O<br />
N<br />
R<br />
Salicylamide<br />
H<br />
H<br />
H<br />
O<br />
R = -CH(CH 3 )C 6 H 4 -p-Br<br />
K i = 0.14 nM<br />
Trp26<br />
HO-Tyr30<br />
HO-Tyr50<br />
O H<br />
H His110<br />
His85<br />
H<br />
N<br />
H<br />
J. M. Chen et al., Biochemistry 37, 17735-17744 (1998)<br />
Hugo Kubinyi, www.kubinyi.de<br />
MeO<br />
OH<br />
OMe<br />
O<br />
OMe<br />
MeO<br />
O<br />
Asn131<br />
N<br />
Quinazoline<br />
His133<br />
N<br />
N H<br />
R<br />
H<br />
H<br />
O<br />
R = -CH 2 CH 2 CH(C 6 H 5 ) 2<br />
K i = 0.15 nM<br />
OMe<br />
N N<br />
MeO<br />
Trp26<br />
HO-Tyr30<br />
HO-Tyr50<br />
O H<br />
H His110<br />
His85<br />
Bioisosterism of Salicylates and Quinazolines<br />
SDZ LAP 977 SDZ LAV 694<br />
IC 50 =<br />
<br />
OMe<br />
N N<br />
47 nM 7 nM 4 nM<br />
(inhibition of tubulin polymerisation; antiproliferative<br />
activity in a keratinocyte cell line)<br />
P. Nussbaumer, Novartis, 17th Int. Symp. Med. Chem., Sept. 2002<br />
O
Hugo Kubinyi, www.kubinyi.de<br />
<strong>Scaffold</strong> Hops Should Consider Pharmacophores<br />
(corticotropin-releasing factor-1 (CRF1) receptor antagonists)<br />
N<br />
N<br />
<br />
N<br />
<br />
N NH<br />
Me Me<br />
Me<br />
N<br />
N<br />
N NH<br />
Cl Cl<br />
Cl<br />
N<br />
N<br />
N NH<br />
Cl Cl<br />
Cl<br />
N<br />
N<br />
N NH<br />
Cl Cl<br />
Cl<br />
N<br />
N N<br />
NH<br />
Cl Cl<br />
Ki CRF1 =<br />
57 nM 70 nM 30 nM 2 nM >10,000 nM<br />
C. Chen et al., J. Med. Chem. 39, 4358-4360 (1996)<br />
Hugo Kubinyi, www.kubinyi.de<br />
<strong>Scaffold</strong> Hops Should Consider Pharmacophores<br />
(binding modes of COX2 inhibitors<br />
to carbonic anhydrase)<br />
N<br />
N<br />
SO 2 NH 2<br />
F 3 C SO2 NH 2<br />
Me<br />
<br />
<br />
O N<br />
Celecoxib<br />
(blue)<br />
Valdecoxib (red)<br />
Me<br />
A. Di Fiore et al., Bioorg. Med. Chem. Lett. 16, 437-442 (2006)<br />
Cl<br />
(1oq5, 2aw1)
Hugo Kubinyi, www.kubinyi.de<br />
<br />
N<br />
NH N NH<br />
N N<br />
1-Phenyl4-Phenyl2-Phenylimidazoleimidazoleimidazole 1.0 . 10 -7 M 4.0 . 10 -5 M 7.0 . 10 -6 M<br />
Hugo Kubinyi, www.kubinyi.de<br />
Me<br />
O<br />
HN<br />
N<br />
O S<br />
NH-tBu<br />
O<br />
Me<br />
O<br />
<br />
O S<br />
N<br />
O<br />
<strong>Scaffold</strong> Hops to „me too“ Analogs<br />
HN<br />
O<br />
N<br />
N<br />
H<br />
N<br />
N<br />
N<br />
early lead structure<br />
(different indication)<br />
O Me<br />
N Et<br />
N<br />
Me<br />
Me<br />
Me<br />
O<br />
O S<br />
N<br />
O<br />
O<br />
HN<br />
HN<br />
O<br />
N<br />
O Me<br />
N<br />
N<br />
N<br />
N Me<br />
N<br />
Me<br />
Me<br />
Sildenafil<br />
Vardenafil Mirodenafil<br />
O S<br />
N<br />
O<br />
Me<br />
N<br />
CH2CH OH 2
Hugo Kubinyi, www.kubinyi.de<br />
<strong>Scaffold</strong> Hops to Chemically Stable Fungicides<br />
Me<br />
O<br />
<br />
OMe<br />
Me<br />
O OMe<br />
strobilurin A<br />
(potent fungicide, unstable)<br />
O<br />
N<br />
OMe<br />
OMe<br />
kresoxim methyl<br />
(BASF)<br />
Hugo Kubinyi, www.kubinyi.de<br />
C<br />
H 3<br />
MeO<br />
C<br />
H 3<br />
Me<br />
O<br />
F<br />
N<br />
HO O<br />
O H<br />
O<br />
CH 3<br />
CN<br />
O<br />
N<br />
O OMe<br />
OMe<br />
first lead structure<br />
(chemically stable)<br />
N<br />
azoxystrobin<br />
(ICI / Zeneca)<br />
A Huge Hop to a Blockbuster<br />
<br />
Lovastatin<br />
OH<br />
OH<br />
O<br />
F<br />
OH<br />
Cerivastatin<br />
(withdrawn)<br />
N<br />
Fluvastatin<br />
OH OH<br />
F<br />
O NH<br />
O<br />
O OMe<br />
N<br />
O<br />
OMe<br />
OH<br />
OH<br />
OH<br />
O<br />
Atorvastatin<br />
OH
Hugo Kubinyi, www.kubinyi.de<br />
Thr-106<br />
R. Buijsman, in H. Kubinyi<br />
and G. Müller, Chemogenomics<br />
in Drug Discovery, Wiley-VCH,<br />
2004, pp. 191-219<br />
Hugo Kubinyi, www.kubinyi.de<br />
O<br />
Met-109<br />
O<br />
HN<br />
N<br />
Gly-110<br />
His-107<br />
<strong>Software</strong> for <strong>Scaffold</strong> <strong>Hopping</strong><br />
N<br />
O<br />
H<br />
Kinase Inhibitors:<br />
Various <strong>Scaffold</strong><br />
Hops to Mimic ATP<br />
H<br />
H<br />
O<br />
Cl<br />
Thr-106<br />
CAVEAT (Paul Bartlett)<br />
CATS and TOPAS (Gisbert Schneider, Roche)<br />
Skelgen (Phil Dean, Roche)<br />
Shop (Ismael Zamora)<br />
FieldStere (Cresset)<br />
BROOD (<strong>OpenEye</strong>)<br />
ReCore<br />
(Matthias Rarey,<br />
BioSolveIT)<br />
N<br />
N<br />
N<br />
Cl<br />
F<br />
N<br />
BR-II<br />
BR-I<br />
F<br />
NH<br />
Asp-168<br />
PBR
Hugo Kubinyi, www.kubinyi.de<br />
Conclusions<br />
<strong>Scaffold</strong> hops are a well-established strategy in lead structure<br />
optimization<br />
<strong>Scaffold</strong> hops offer new opportunities and chances<br />
- enhancement of biological activity<br />
- modulation of selectivity<br />
- modulation of physicochemical properties<br />
- intellectual property of „me too“ analogs<br />
Cave: modification of the pharmacophore may change the<br />
binding mode<br />
<strong>Software</strong> should stimulate your creativity<br />
“whenever people turn on the computer, they are tempted to<br />
switch off their brain at the same time, relying too much on<br />
some intelligence within the (commercial) programs”<br />
quoted from Nature Rev. Drug. Discov. 2, 665-668 (2003)<br />
Hugo Kubinyi, www.kubinyi.de<br />
Selected References<br />
G. Lauri and P. A. Bartlett, CAVEAT: A program to facilitate the design<br />
of organic molecules, J. Comput.-Aided Mol. Design 8, 51-66 (1994).<br />
G. Schneider, W. Neidhart, T. Giller and G. Schmid, "<strong>Scaffold</strong>-hopping"<br />
by topological pharmacophore search: a contribution to virtual<br />
screening, Angew. Chem. Int. Ed. Engl. 38, 2894-2896 (1999).<br />
D. G. Lloyd, C. L. Buenemann, N. P. Todorov, D. T. Manallack and<br />
P. M. Dean, <strong>Scaffold</strong> hopping in de novo design. Ligand generation in<br />
the absence of receptor information, J. Med. Chem. 47, 493-496 (2004).<br />
S. Renner and G. Schneider, <strong>Scaffold</strong>-hopping potential of ligand-based<br />
similarity concepts, ChemMedChem 1, 181-185 (2006).<br />
P. Maass, T. Schulz-Gasch, M. Stahl and M. Rarey, Recore: a fast and<br />
versatile method for scaffold hopping based on small molecule<br />
crystal structure conformations, J. Chem. Inf. Model. 47, 390-399 (2007).