phase II
5
clinical study
phase I
10
clinical study
preclinical
20
studies
0 2 4 6 8 10 12
Years
Summer School on Drug Design and Molecular Modeling
Istanbul, September 10-14, 2008
Efficiency Deficit ...
800 Mio $
1
>> 100.000
150 Mio $
800 Mio $
1
>> 100.000
150 Mio $
1 – Start screening with a limited set of carefully chosen, structurally diverse, drug
molecules (a smart library of about 1000 compounds). Already bioavailability and
toxicity studies have been performed and as they have proven usefulness in human
therapy, all hits that will be found are “drug-like”!
In other words, if they are able to exert a strong interaction with the
main target, they exert also less strong interactions with some other
biological targets. Most of these targets are unrelated to the primary
therapeutic activity of the compound.
Real 3D
1D Filter 2D Filter 3D Filter
Fitting
Real 3D
1D Filter 2D Filter 3D Filter
Fitting
1D Filter
– properties
– fingerprints
e.g. MW 200-500
Ro5 / Lipinski
Real 3D
1D Filter 2D Filter 3D Filter
Fitting
1D Filter 2D Filter
– properties – topology, mol.
– fingerprints graphs
– (red. graphs,
FTrees, …)
e.g. MW 200-500
Ro5 / Lipinski
Real 3D
1D Filter 2D Filter 3D Filter
Fitting
Real 3D
1D Filter 2D Filter 3D Filter
Fitting
Real 3D
1D Filter 2D Filter 3D Filter
Fitting
against
10 targets
x
• Universal
- Pharmacophore models represent chemical functions,
valid not only for the currently bound, but also unknown
molecules
• Computationally Efficient
- Due to their simplicity, they are suitable for large scale virtual
screening (>109 compounds, also in parallel settings)
Methotrexate Dihydrofolate
Methotrexate Dihydrofolate
Methotrexate Dihydrofolate
Methotrexate Dihydrofolate
Methotrexate Dihydrofolate
Methotrexate Dihydrofolate
Wrong
Correct
1RX2
1RB3
1RX2
1RB3
1RX2
1RB3
Is pairing valid?
If not, remove invalid pairs and retry
Acceptor
Donor
Lipophilic
Acceptor 0|0|1
Donor
Lipophilic
Acceptor 0|0|1
Donor 0|1|1
Lipophilic
Acceptor 0|0|1
Donor 0|1|1
Lipophilic 0|1|1
Acceptor 0|0|1
Donor 0|1|1
Lipophilic 0|1|1
Acceptor 0|0|1
Donor 0|1|1
Lipophilic 0|1|1
1 1
1 1
3 4
2
5
5
3
4
1 1
3 4
2
5
5
3
4
1 1
2ivv 2ivu
- 5 viral targets
- 50 pharmacophore models
HIV reverse transcriptase HIV infection, Synthesis of a virion DNA, Inhibition at allosteric site
(RT) AIDS integration into host DNA and
transcription
Human rhinovirus (HRV) Common cold Attachment to host cell receptor, Binding in hydrophobic pocket
coat protein viral entry, and uncoating (capsid stabilization)
Hepatitis C virus (HCV) Hepatitis C Viral replication, transcription of Inhibition at various allosteric
RNA polymerase genomic RNA sites
Ratio ≥ 1
90% of the compounds
correctly predicted
Ratio < 1
8% more often
predicted for one
specific false target
than for correct one
for 2% of the
compounds no activity
prediction possible
HIV RT
Influenza NA
HRV coat
protein
HCV
polymerase
123
HIV RT
Influenza NA
HRV coat
protein
HCV
polymerase
123
HIV RT
Influenza NA
HRV coat
protein
HCV
polymerase
123
HIV RT
Influenza NA
HRV coat
protein
HCV
polymerase
123
Model with lowest selectivity: Model with 85% hit rate Model with highest selectivity:
70% of actives (HIV RT), but 75% from one specific 100% of actives (HCV polymerase 1),
false target (HRV coat protein) 100% active and 0% inactive
40% active and 60% inactive compounds in hit list compounds in hit list
correct false
no data or negative
not applicable
false
positive
Results Matrix
Compound 1A2-S 1A2-L 2C9-S 2C9-L 2C19-S 2C19-L 2D6-S 2D6-L 3A4-S 3A4-L resc.
clozapine n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. +/+
naproxen +/+ n.d. +/+ n.d. -/+ n.d. -/+ n.d. -/- n.d. -/-
miconazole n.d. +/+ n.d. +/+ n.d. +/+ n.d. +/+ n.d. +/+ -/-
citalopram n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. +/+
mirtazapine n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. +/+
delavirdine -/- -/+ -/+ +/+ -/+ +/+ +/+ -/+ +/+ +/+ -/-
aprepitant -/+ +/- -/- -/+ +/+ +/+ -/+ -/+ +/+ +/+ -/-
efavirenz +/+ +/+ -/- +/+ -/+ +/- -/- +/+ +/- +/- -/-
estazolam -/+ n.d. -/- n.d. -/+ n.d. -/- n.d. +/+ n.d. -/-
fluconazole n.d. -/+ n.d. +/+ n.d. +/- n.d. -/- n.d. +/- -/-
itraconazole n.d. -/- n.d. -/- n.d. -/- n.d. -/- n.d. +/+ -/-
nevirapine -/+ -/+ -/- -/+ -/+ -/- +/+ -/+ +/- -/- -/-
oxatomide -/- -/+ -/- -/- -/+ -/- +/+ +/+ +/- +/- -/-
SCH-351125 -/- n.d. +/+ n.d. -/- n.d. -/+ n.d. +/+ n.d. -/-
TR-14035 -/- n.d. +/+ n.d. -/+ n.d. -/- n.d. -/+ n.d. -/-
voriconazole -/+ -/+ +/+ +/+ +/+ +/+ -/- -/+ +/+ +/- -/-
ziprasidone -/+ -/+ -/- -/+ -/+ -/+ -/+ +/+ +/+ +/+ -/-
6% P450 3A4
Some Special Considerations
•e.g. ketoconazole / Cyp P450 3A4 (pdb 2v0m)
Some Special Considerations
•e.g. ketoconazole / Cyp P450 3A4 (pdb 2v0m)
Development of special
Fe-binding pharmacophore
feature in LigandScout 2.0
Analysis of PDB
•Distance Fe - Ligand
heme-ligands non-heme-ligands
Nonsteroidal
3 23 19 40 48 100 25
with restrictive 149,78
(60%) (56%) (0,028%) (0,067%) (0,039%) (0,046%) (0,2%)
Fe-Feature
Nonsteroidal
3 22 216 442 983 770 213
with HBA- 29,26
(60%) (54%) (0,32%) (0,74%) (0,8%) (0,36%) (1,67%)
Feature
New Feature Boosts Enrichment ...
Training Test
WDI Maybridge NCI Specs Virtual
Hypothesis Set Set
(67050) (59652) (123219) (216823) DB
(4) (70)
Steroidal
4 37 15 0 2 1 0
with new
(100%) (53%) (0,02%) (0%) (0,002%) (0,0005%) (0%)
Fe-Feature
K. Chuang
J. Benedict
N. Triballeau-Hugounencq
Rémy D. Hoffmann
Results indicate
• Correct assignment of selectivity in most cases
• Independent of search algorithms used
Results indicate
• Correct assignment of selectivity in most cases
• Independent of search algorithms used
• Represented in
~ 200 ligand-based pharmacophore models
~ 2300 structure-based pharmacophore models
www.prestwickchemical.com
www.inteligand.com