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Sequential Screening
S. Stanley Young
NISSHTS Workshop
October 25, 2002
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What are the problems?
HTS data sets are very large.
Mixture of mechanisms.
Bioassay data measured with error.
Search space is very large.
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StatisticalAnalysis
CorporateCollection
CommercialCompounds
VirtualCompounds
Statistical Model
SelectedCompounds
InitialCompounds
ActiveCompounds
Filters
ScreenCompounds
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Find Multiple Chemical Classes
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Separate Mixture into Components
10,000 x 20,000
Inactives
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MAO Inhibitors
NH
HN
N
O
O
C NCH
NN-CC
C(3,1)-6-C(1,2)
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Individual versus Group(Compound versus Feature)
0 31 2 4 5 6-1-2-3
0 31 2 4 5 6-1-2-3
0 31 2 4 5 6-1-2-3
Individual observations
Distributions of meansof 10 observations
Distributions of meansof 25 observations
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Small Shifts = Big Gains
-40 -20 0 20 40 60 80 100
N= 372
-40 -20 0 20 40 60 80 100
N=23,232Initial
ScreeningSet
SelectedCompounds
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Enrichment Results
Assay Training Pachinko Ratio#1 0.26 6.18 24x#2 0.6 0.3 Fail*#3 2.2 22.3 10x#4 2.1 15.0 7x#5 9.4 5.2 Fail*#6 2.6 42.5 16x#7 0.4 15.3 38x #8 0.16 1.5 9x
* Assay not stable over time.
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Descriptors
1. Capture relevant chemical information.
2. Fast to compute.
3. Easy to interpret.
4. Not too many.
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Memorize versus Generalize
Atoms / Functional Groups :
-OH O(1,0) O(C ) HBD HBA
=O O(1,1) O(C ) HBA
Molecular twins in data sets.
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Definition of TermsExample: Pharmacophores for estrogen receptor (ER)
– 1D:
Molecular Volume: 346.47 Å
– 2D:
– 3D:
OH
H
H
H
[H,A]
[H,A]
H-bondDonor
H-bondAcceptor
A
AA
A
AA
7-10Å
2.5-4Å
10-14Å
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D E
A B C
Conformer 1
X
Y
Z
RW
Y
S V
Example of a conformer fingerprint
………..
FingerprintNumber
1 2 3 4 5 6 7 8 10547 10548 10549
01 1 1 1 0 00 0 0 1
PharmPrint: Theory
C
A BX
YZ
D
A CX
YZ
D
A BX
YZ
C
A BW
YZ
D
A CW
YZ
E
D BW
YR C
D BW
YR
Conformer 1
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Fragment Molecular DescriptorsAtom pair
N(3,0) - 7 - S(2,0)
Atom triple
N(3,0) - 7 - S(2,0)
S(2,0) - 6 - N(2,0)
N(3,0) - 12 - N(2,0)
Topological torsion
N(3,0)C(2,0)-1-C(3,1)O(2,0)
ON S
HN
NO
ONH
ON S
HN
NO
ONH
ON S
HN
NO
ONH
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Fragment Molecular Descriptors
Augmented Atoms
N(CCC), S(CC)
Augmented Atom Pair
N(CCC) - 6 - S(CC)
ON S
HN
NO
ONH
ON S
HN
NO
ONH
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Carry out Partial Least Squares Analysis (PLS)
Use both active compounds and inactive compounds
PharmPrint : Theory
Cx-1
11 1 0 0 0 00 0 0 0Molecule 3
01 0 1 0 0 00 0 0 0Molecule 2
….. 11 1 1 1 0 00 0 0 1Molecule 1
11 1 1 1 1 00 0 0 0Molecule X
11 0 1 1 0 00 0 0 0Molecule X-1
::
::
…..
…..
…..
…..
1
1
1
0
0
::
3-point Fingerprints ActivitiesCoefficients
C3
C2
C1
Cx
::
=X
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Example Catalyst Pharmacophore Features
AliphaticHydrophobe
Hydrogen bond acceptor
Aromatic Hydrophobe
Hetero-atom
Projected location of hydrogen
Aromatic Ring
Hydrogen bond donor
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Model of AR Binding Site (Cool Picture)
ARG752
GLN711
ASN705
2.94 Å
3.04 Å
2.79 Å
3.24 Å
10.50 Å