Professional Documents
Culture Documents
de
Changing Paradigms
in Drug Discovery
Hugo Kubinyi
Germany
E-Mail kubinyi@t-online.de
HomePage www.kubinyi.de
Experiments in humans
(J. Lind, 1747, treatment of scurvy)
con: toxicity
Hugo Kubinyi, www.kubinyi.de
Animal experiments
H
S
RHN „Penicillin
N happened,
O COOH it came out
of the blue.“
A. Fleming,
1930
Hugo Kubinyi, www.kubinyi.de
(n = 974)
presynaptic
nerve cell
Ca2+
MAO dopamine
inactive transporter
metabolites
synaptic gap
postsynaptic
nerve cell postsynaptic
membrane
dopamine receptor
with G-protein complex
con: no ADMET
single target
Chemical biology
Chemogenomics
pro: multitarget-oriented
quick information on
selectivity
con: no ADMET
N NC
NH O OMe
NH2 CHO
HN
O
N N
HN NC
(Me)2N
O N
MeO O
OMe O COSH
T.T. Ashburn and K.B. Thor, Nature Rev. Drug Discov. 3, 673-683 (2004)
is no hit thousands
# is no lead dozens
optimization: thousands
is no candidate some
is no drug 1
Hugo Kubinyi, www.kubinyi.de
A. Cressy Morrison
pharmacophores, structure-based
(3D) similarity, design
(3D) QSAR
LBLD SBLD
Thrombin-Thrombstop Complex
Hugo Kubinyi, www.kubinyi.de
O O
H - -
N O O
{ N + HO +
H NH2 NH2
O O
R
H2N N H2 N N
substrate H
inhibitor H
CH3
HOOC N HS N
O COOH O COOH
IC50 = 330 µM Captopril IC50 = 23 nM
HO OH
phospholipase
inhibitor HO OH
CH3 CH2 N N
O
MeO HIV protease
inhibitor
O OH
O O N COOH
O COOH
S HO
N OH
H AcNH
O N HN NH2
H
N
neuraminidase NH
thrombin inhibitor HN NH2 inhibitor
Hugo Kubinyi, www.kubinyi.de
Influenza
In 1918/19, the „Spanish Flu“
killed about 20-40 mio people.
Especially young and very old
people died from influenza.
The heavy death toll of this
pandemic disease has to be
compared to the number of
11 mio victims of World War I.
Egon Schiele prepared this
drawing of his wife, one day
before her death and four days
before he died himself, only
28 years old.
Influenza Virus
schematic view
and electron micro-
scopic picture
Hugo Kubinyi, www.kubinyi.de
+
Glu-119 Glu-227
Hugo Kubinyi, www.kubinyi.de
α $ hERß
hERα
„upper“ side:
Leu384 $ Met336
„lower“ side:
Met421 $ Ile373
A. Hillisch et al., Ernst Schering Res. Found. Workshop 46, 47-62
(2004); A. Hillisch et al., Mol. Endocrinol. 18, 1599-1609 (2004)
Hugo Kubinyi, www.kubinyi.de
Property Filters
(MW, rule of 5, rot, drug-like, ...)
1D Pharmacophore and
3D Pharmacophore Searches
N F
H N
N
N
N
O S
α 1A adrenergic receptor antagonist, Ki = 1.4 nM
Fragment-
based Design
of a Thrombin
Inhibitor
OMe
O
O S
OMe HN
N N
O
N N HO
O S
+ NH
HN N N
Cl N N
HO IC50 = 100 µM
NH2 Cl
IC50 = 12 µM IC50 = 1.4 nM
11%
30% Pharmacokinetics
R. A. Prentis et al., Lack of efficacy
Br. J. Clin. Pharmacol. Animal toxicity
25, 387-396 (1988); Adverse effects in man
T. Kennedy, Drug Discov. Commercial reasons
today 2, 436-444 (1997) Miscellaneous
Hugo Kubinyi, www.kubinyi.de
data from
W. K. Sietsema, Int.
J. Clin. Pharmacol.
27, 179-211 (1989)
Hugo Kubinyi, www.kubinyi.de
46%
17%
Pharmacokinetics
R. A. Prentis et al., Lack of efficacy
Br. J. Clin. Pharmacol. Animal toxicity
25, 387-396 (1988); Adverse effects in man
T. Kennedy, Drug Discov. Commercial reasons
today 2, 436-444 (1997) Miscellaneous
Dog
red triangles
Primates
blue squares
data from:
W. K. Sietsema,
Int. J. Clin.
Pharmacol. 27,
179-211 (1989)
The Role of
Transporters in
Drug Uptake
and Elimination
H. Gleaser et al.,
in R. J. Vaz and
T. Klabunde,
Antitargets,
Wiley-VCH, 2008,
pp. 341-366
O O OH
IC50 = 0.8 nM (human)
O
H 1.0-1.7 nM (monkeys)
S N
N 107 nM (dog)
H 3 600 nM (rat)
O OH
N NH
N Rat 16.5
CH3
H Rabbit 0.3
Elephant « 0.06
HN
LSD
Man » 0.003
healthy volunteers,
age 18-55 years,
males and females
(however, no females
who could be or could
become pregnant),
normal weight, no
smokers, no alcohol
(ab)use, standard
food, drug taken with
150 ml water, no other
therapy, no intake of
fruit juices or illegal
drugs.
The Patients
The Past
Voltaire (1694-1778):
Doctors
pour drugs of which
they know little,
to cure diseases of which
they know less,
into human beings
of whom
they know nothing.
Voltaire, by J. A. Houdon