SARNavigator &HTS data analysis
Tripos Inc.
09/02/03

HTS Workflow
Screening
DeckHTSPrimary
HTS data

Screening
QA

RefinedHTS dataSeries
definition

Seriesexpansion

Series2o expansion
screenPriorityseries

All chemicalseries
Seriesprioritisation

Secondaryscreen data
SARNavigator
LeadOptimization

Chemical Series•

Goal: definition of chemical series from HTS
data for continued researchoo•Secondary screening, follow up chemistryFirst stage of hit
lead

What defines a chemical series?
ocommon core/synthetic pathway/what I say, …?
Structural similarity(substructure, fingerprint, chemistry intuition …)

Biological Similarity(Activity, Selectivity, …)

ChemicalSeriesExploratory Data Analysis“I don’t know exactly what I’m looking for - but I’ll
know when I see it!”•… chemist (reviewing HTS results)

EDA Methods:
ovisual analysis of hit structures––oclustering and cluster analysis––ohierarchical/non-hierarchical clustering clustering
data quality is paramount/use of negative data/chemical series?

structural property/activity visualization––

ochemists with print-outs of hit structuressubjective/slow/irreproducablemultidimensional graphs
relationship to actual structures/view of all relevant data?

Visualisation of high-D spaces–NLM/MDS to reduce dimensionality

Visualisation of HTS Data•

View entire SAR landscapeo2D plot of HTS data–oo•such that similar compounds are close on the plot
map activity and other data onto plotted points

Uses combination of clustering and PCA/NLM
ooooo

•

either clusters or compounds

select diverse, representative compounds (signposts)
other compounds partitioned into signpost clusters
run PCA/NLM on signpost properties and plot
similar clusters will be close to each otheruser can drill down into clusters

Only care about local similarity

PCA/NLM Plots with Horizon

SAR Landscape view
Signpostcompounds

PCA/NLMsimilarity map

Selectedcompounds
Selectedstructuresproperty
mappingSARNav data visualisations

Scatter plots with data mapping

Bullseye plot
- single compound
similarity neighbourhood

Histograms
Correlation coefficients

Series Definition•

Interactive series definition
oooo•

Series trackingooo•

selected cluster(s)selected compounds
from substructure searchfrom property ranges

series viewer
series annotation
series ranking

Connection to SeriesBase

Series Prioritisation•Visual analysisobiologist–ochemist–•might these compounds have interfered with the screen?
what are the prospects for further chemical modification?

HQSAR
ooo

can a QSAR model be produced for the series
does HQSAR tell us anything about the SAR
rapid predictive QSAR–

based on molecular holograms

Series Prioritisation•Is there any obvious SARo•

if so this may be a good series for 2º screening

R-group deconvolutionoodetermines scaffold through MCS calculation
splits structures into scaffold + R-groups

Series Expansion•Once series have been defined and prioritisedo•

find other compounds that may be suitable forfurther evaluation

Expand series withooo

clusters close to/between defined series
compounds with similar/R-groups scaffolds
compounds from outside the screening deck

SARNavigator Workflow
Import data
Filter data
Cluster hits
Add non hits to clusters

Initial series
exploration
Reexamine
series withinactives

Define series
Prioritise series
Expand series

SAR, QSAR
property
data
Substructure
searchingNCI H23 screen - example•

National Cancer Institute Human Tumor dataset•

Only one cell line usedo•

NCI-H23 (non small cell lung)

Activity data pGI50o-log concentration at 50% growth inhibition•

35000+ compounds•

Activity threshold: pGI50 ≥ 6 (1848 actives)•All compounds used

H23 - Actives Partitioned

Mean cluster activityLow

High

Mean cluster Lipinski violations<22-3>3Points sized by cluster sizeIncluding the inactives
ooopartition actives into clusters and projectadd inactives to active clusters
compare active vs. active & inactive projections

BeforeActives Only

After
Actives & Inactives
colour - %active cmpds in cluster

Summary•

SARNavigatorooo

Support for HTS data analysis
Raw HTS dataprioritised chemical series
Modification and extension