1 Sequential Screening S. Stanley Young NISS HTS Workshop October 25, 2002

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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