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“INTEGRATED CONCEPT” for

INSILICO SCREENING & DRUG DESIGN

湯田 浩太郎 Kohtaro Yuta

In Silico Data, Ltd.

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012

ACTIVITY, ADME, TOXICITY, PROPERTY ANALYSIS AND PREDICTION

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012

Application pattern of integrated concept “Integrated in silico screening”

“Integrated in silico drug design”

2

“Integrated” concept 1

Multivariate and pattern recognition From pattern analysis to scientific analysis

High classification and prediction rate by

KY-methods and Tailor made modeling

3

“Integrated” concept

O

N

O

O

Pharmacological activity

Physico chemical properties

ADME properties

Toxicity

Drug properties and compound structure

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“Integrated” concept “Integrated” concept for drug development

Activity + ＡＤＭＥ + Toxicity + Property

“ Integrated” concept

All drug properties shall be considered at the same time

“ Integrated” in silico screening & drug design

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012

4

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012

Application pattern of integrated concept “Integrated in silico screening”

“Integrated in silico drug design”

2

“Integrated” concept 1

Multivariate and pattern recognition From pattern analysis to scientific analysis

High classification and prediction rate by

KY-methods and Tailor made modeling

3

Two application style of “Integrated”

In silico screening

“Integrated” concept

“Integrated in silico screening”

Multi-dimensional in silico screening

In silico drug design

“Integrated in silico drug design”

Interactive in silico drug design

“Integrated” concept

Application pattern of integrated concept

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“Integrated” in silico screening

One-dimensional screening

one activity／compound

Multi-dimensional screening multiple activities ” ADME ” toxicities ” properties compound

Conventional approach

Next-generation approach

Application pattern of integrated concept

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Application pattern of integrated concept

“Interactive and real-time” drug design

Starting compound antibacterial Anti-infla

mmatory anticancer ・ ・ ・ ・ ・ pesticide

carcinogenicity Ames test ＬＤ５０ ・ ・ ・ ・ ・ others ＡＤＭＥ and properties Ｃａｃｏ－２ ＢＢＢ ＣＹＰ ＬｏｇＰ ｐＫａ ＬｏｇＤ７．４

Modified compound

I

II

O

O

H

N

H

H

H

H

H

HH

H

H

H

H

I

I

O

O

H

N

H

H

H

H

H H

H

H

H

H

H

H

modification activity ADME toxicity

property

Information on different properties of different compounds is available anytime

＊Check the effects of structure modifications on compound properties real-time

antibacterial Anti-inflammatory

anticancer ・ ・ ・ ・ ・ pesticide

carcinogenicity Ames test ＬＤ５０ ・ ・ ・ ・ ・ others

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4

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012

Application pattern of integrated concept “Integrated in silico screening”

“Integrated in silico drug design”

2

“Integrated” concept 1

Multivariate and pattern recognition From pattern analysis to scientific analysis

High classification and prediction rate by

KY-methods and Tailor made modeling

3

Black box Compounds

Activity Toxicity ADME Property Others

parameters Used parameters Objective

Information equivalence

Basic priniciple of data analysis by MVA & PR

Multivariate and pattern recognition

Relationship information

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Simple classification and scientific classification

Feature selection

Neural network

Recursive partitioning

Ｎ

Ａ

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Ａ Ａ

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Ａ

Ｎ Ｎ Ｎ

Ｎ Ｎ

Ｎ Ｎ

Ｎ

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Ｎ

Ａ Ａ

Ａ

Ａ

Ａ

Ａ

Ｎ Ａ

Ａ Ｎ

Pattern space impossible to be classified by linear discriminant

Classified by pattern space

Linear discriminant

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Ａ Ａ

Ａ Ａ

Ａ Ａ

Ａ

Ａ Ａ

Ａ

Ｎ Ｎ

Ｎ

Ｎ Ｎ

Ｎ Ｎ Ｎ Ｎ

Pattern space classified by linear discriminant

Ｎ Ｎ

Ａ Ａ Ａ

Ａ Ａ

Classified by scientific reasons

ADMEWORKS

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Ｓ

Ｓ

Ｓ

Ｓ

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Ｓ Ｓ Ｓ

Ｓ

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Ｓ Ｓ Ｓ

Ｓ

Ｓ Ｓ

Ｓ Ｓ Ｓ

Ｓ Ｓ Ｓ

Ｓ

Ｓ

Ｓ

Ｓ Ｕ

Y=a1x1+a2x2+・・+anxn+const.

Ｓ outlier

Interpolation

Extrapolation Science based approach

Ｓ Ｓ

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Fitting by Neural Networks

R=0.99>R=0.70

Which is true outlier?

Linear regression line

Extrapolation

Extrapolation

No science based approach

Feature selection

ADMEWORKS

Simple fitting and scientific fitting

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012

4

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012

Application pattern of integrated concept “Integrated in silico screening”

“Integrated in silico drug design”

2

“Integrated” concept 1

Multivariate and pattern recognition From pattern analysis to scientific analysis

High classification and prediction rate by

KY-methods and Tailor made modeling

3

湯田 浩太郎 Kohtaro Yuta

In Silico Data, Ltd.

All Rights Reserved, Copyright (C) IN SILICO DATA, Ltd. 2012