USING ELSEVIER’S LIFE SCIENCE SOLUTION PORTFOLIO IN EXPLORING DRUG TARGETS FOR SCHIZOPHRENIA

Jim Rinker

Customer Consultant

Elsevier

6/30/15

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Report

Analyze SAR

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ELN

Docs

Content

Intellectual Property

Clinical Studies

Docs

Therapeutic

targets

Knowledge

survey Known ligands

DRUG DISCOVERY PROCESS Text Mining & Data Integration

Biology

Generate chemistry ideas

UNDERSTANDING DISEASE TARGETS AND INHIBITORS

Cell Process

Disease

Target

Small

Molecule

Side Effect Scaffold

Understanding how targets relate to cell processes, small molecules, diseases, and side

effects from either the drug or target inhibition is critical to the success of a drug discovery

project

Target Class

Tissue Distribution

WEBINAR OVERVIEW OVERVIEW

1. Find key regulators responsible for symptoms of Schizophrenia

2. Correlate known antipsychotic drugs to these regulators

3. Review known “target-effect” and “target-side effects” for regulators

4. Determine biological target(s) responsible for select side effects using

Pathway Studio

5. Validate literature findings using clinical data in Pharmapendium

6. Expand our knowledge on known relationships we found by using our

life sciences text mining solution and Embase

7. Study the SAR of antipsychotics vs. select targets using Reaxys

Medicinal Chemistry

8. Use this information to aid in the design of future antipsychotics

devoid of select side effects

9. Use LSS portfolio to create a PV/Safety solution

SCHIZOPHRENIA OVERVIEW

Schizophrenia (/ˌskɪtsɵˈfrɛniə/ or /ˌskɪtsɵˈfriːniə/) is a mental disorder often

characterized by abnormal social behavior and failure to recognize what is real.

Common symptoms include false beliefs, unclear or confused thinking, auditory

hallucinations, reduced social engagement and emotional expression,

and inactivity.

Schizophrenia is often described in terms of positive and negative (or deficit)

symptoms.

Positive symptoms are those that most individuals do not normally experience

but are present in people with schizophrenia. They can include delusions,

disordered thoughts and speech, and tactile, auditory, visual, olfactory

and gustatory hallucinations, typically regarded as manifestations

of psychosis.

Negative symptoms are deficits of normal emotional responses or of other

thought processes, and respond less well to medication.They commonly

include flat expressions or little emotion, poverty of speech, inability to

experience pleasure, lack of desire to form relationships, and lack of motivation.

PATHWAY STUDIO OVERVIEW

MedScan reads scientific literature and extracts described relations between biological

concepts such as proteins, small molecules, diseases and cell processes

Databases Mammal, Plant, ChemEffect,

DiseaseFx, Custom

Relation Extraction

from literature

MedScan

• >4.7 million relations and >28 million biological facts

supported by >15 millions sentences,

• From >4.1 million full text articles from 1600 journals and >24

million PubMed Abstracts.

• 10,000 total journal titles covered from Elsevier and other

leading publishers.

Biological Relations

PATHWAY STUDIO OVERVIEW

MedScan – How it works

Input Text (MedScan extracts from within a sentence):

“Axin binds beta-catenin and inhibits GSK-3beta.”

Identify Proteins in Dictionary (in red): [Entities]

“Axin binds beta-catenin and inhibits GSK-3beta.”

Identify Interaction Type (in black): [Relationships] “Axin binds beta-catenin and inhibits GSK-3beta.”

Extracted Facts (added to database):

Axin - beta-catenin relation: Binding Axin -> GSK-3beta relation: Regulation, effect:

Negative

PATHWAY STUDIO OVERVIEW

MedScan reads scientific literature and extracts described relations between biological

concepts such as proteins, small molecules, diseases and cell processes

Search the taxonomy in PS for proteins,

diseases, small molecules

Search the taxonomy in PS for proteins,

diseases, small molecules

PATHWAY STUDIO OVERVIEW

MedScan reads scientific literature and extracts described relations between biological

concepts such as proteins, small molecules, diseases and cell processes

Find disease/regulator relationships

Filter by one or multiple criteria

Check the desired entity(ies) Map entities by specific relationships

DETERMINING KEY REGULATORS OF SCHIZOPHRENIA Pathway Studio was used to determine key regulators of Schizophrenia based on literature

precedence. These regulators are organized based on target class.

Click on line

DETERMINING KEY REGULATORS OF SCHIZOPHRENIA Pathway Studio was used to determine key regulators of Schizophrenia based on literature

precedence. These regulators are organized based on target class.

Click on line

Link to Pubmed Abstract

MAPPING KNOWN SCHIZOPHRENIA DRUGS TO REGULATORS

The ChemEffect module in Pathway Studio was used to find all drugs marketed for

Schizophrenia and map them to the disease regulators. Extraneous regulators were removed

from the pathway

MAPPING KNOWN SCHIZOPHRENIA DRUGS TO REGULATORS

The ChemEffect module in Pathway Studio was used to find all drugs marketed for

Schizophrenia and map them to the disease regulators. Extraneous regulators were removed

from the pathway

CONSENSUS REGULATORS

Mapping of antipsychotic drugs to regulators reveals two distinct classes

Dopamine Serotonin

SIDE EFFECTS FROM DOPAMINE RECEPTOR REGULATION

The Disease Effect module in Pathway Studio was used to determine all effects and side effects

for Dopamine receptors modulated by known Schizophrenia drugs. Side effects are highlighted

in red while effects are highlighted in green.

Click on line

SIDE EFFECTS FROM DOPAMINE RECEPTOR REGULATION

The Disease Effect module in Pathway Studio was used to determine all effects and side effects

for Dopamine receptors modulated by known Schizophrenia drugs. Side effects are highlighted

in red while effects are highlighted in green.

Click on line

SIDE EFFECTS FROM DOPAMINE RECEPTOR REGULATION

The Disease Effect module in Pathway Studio was used to determine all effects and side effects

for Dopamine receptors modulated by known Schizophrenia drugs. Side effects are highlighted

in red while effects are highlighted in green.

SIDE EFFECTS FROM DOPAMINE RECEPTOR REGULATION

The Disease Effect module in Pathway Studio was used to determine all effects and side effects

for Dopamine receptors modulated by known Schizophrenia drugs. Side effects are highlighted

in red while effects are highlighted in green.

SIDE EFFECTS FROM SEROTONIN 5-HT RECEPTOR REGULATION

The Disease Effect module in Pathway Studio was used to determine all effects and side effects

for 5-HT receptors modulated by known Schizophrenia drugs. Side effects are highlighted in

red while effects are highlighted in green.

SIDE EFFECTS FROM SEROTONIN 5-HT RECEPTOR REGULATION

The Disease Effect module in Pathway Studio was used to determine all effects and side effects

for 5-HT receptors modulated by known Schizophrenia drugs. Side effects are highlighted in

red while effects are highlighted in green.

CONTRAST BETWEEN HTR1A AND 2A RECEPTOR REGULATION

The Disease Effect module in Pathway Studio was used to determine which serotonin 5-HT

receptors were most important in the regulation of Schizophrenia.

The literature supports the need for a HTR1A

agonist but HTR2A antagonist to treat

Schizophrenia

COGNITIVE SIDE EFFECTS VS TARGET MODULATION

Multiple serotonin and dopamine receptors have a direct effect on cognition

COGNITIVE EFFECTS OF ANTIPSYCHOTIC DRUGS

PHARMAPENDIUM OVERVIEW

Pharmapendium extracts data from FDA and EMA approval documents, FDA AERS reports, and

journal articles to create a searchable database of clinical facts

PHARMAPENDIUM OVERVIEW

Pharmapendium has multiple modules to compare drugs or drug targets and associated data

such as PK data, metabolic enzymes, transporters, and adverse events.

Search Pharmapendium for drug-adverse event

relationships

USING PHARMAPENDIUM TO FIND REPORTED ADVERSE EVENTS

The drug safety module in Pharmapenium allows you to search for a drug, drug class, or drug

target in relation to one or multiple adverse events

USING PHARMAPENDIUM TO FIND REPORTED ADVERSE EVENTS

An example of adverse event data found on cognitive disturbance for the antipsychotic drug

USING PHARMAPENDIUM TO FIND REPORTED ADVERSE EVENTS

A summary report allows for direct comparison of a drug class and the number of reported

adverse events

ENHANCING OUR RESULTS VIA EMBASE

Embase is a biomedical search tool that searches 8400+ journals reviewed and indexed by

biomedical professionals and can be used to provide further insight to the connection between

antipsychotic drugs and cognitive side effects via a more comprehensive literature search

ENHANCING OUR RESULTS VIA EMBASE

Embase is a biomedical search tool that searches 8400+ journals reviewed and indexed by

biomedical professionals and can be used to provide further insight to the connection between

antipsychotic drugs and cognitive side effects via a more comprehensive literature search

Indexing using our Emtree taxonomy allows for comprehensive

literature searching

ENHANCING OUR RESULTS VIA TEXT MINING

Elsevier’s text mining solution can be used to provide further insight to the connection between

antipsychotic drugs and cognitive side effects

ENHANCING OUR RESULTS VIA TEXT MINING

Elsevier’s text mining solution can be used to provide further insight to the connection between

antipsychotic drugs and cognitive side effects

COGNITIVE EFFECTS VS DRUG TARGETS

The Disease Effect module in Pathway Studio was used to find the key regulators associated

with both Schizophrenia and cognitive disorders and impairment

COGNITIVE EFFECTS VS DRUG TARGETS

The Disease Effect module in Pathway Studio was used to find the key regulators associated

with both Schizophrenia and cognitive disorders and impairment

COGNITIVE EFFECTS VS DRUG TARGETS

The Disease Effect module in Pathway Studio was used to find the key regulators associated

with both Schizophrenia and cognitive disorders and impairment

TARGET CONSENSUS

Using the fore mentioned information, a consensus model was built for targets essential for the

modulation of both symptoms and key side effects of known Schizophrenia drugs. These

targets were then ported into Reaxys Medicinal Chemistry for further analysis.

Target Consensus

TRANSLATING RESULTS TO RMC FOR EVALUATION

In addition to the key Schizophrenia targets, a battery of other CNS receptors was also created

to determine any known “off target” activity for compounds inhibiting the Schizophrenia

targets. This information can be used to do SAR and dial out off target activity.

cholinergic receptor, nicotinic, alpha 7

Histamine 1 receptor

Histamine 2 receptor

Histamine 3 receptor

Histamine 4 receptor

Alpha 1a adrenergic receptor

Alpha 1b adrenergic receptor

Alpha 2c adrenergic receptor

Alpha 2b adrenergic receptor

Alpha 2a adrenergic receptor

Alpha 2 adrenergic receptor

DAT

monoamine oxidase a

monoamine oxidase b

metabotropic glutamate 5

adenosine a2 receptor

cannabinoid 1 receptor

5-hydroxytryptamine 1a receptor

5-hydroxytryptamine 2a receptor

5-hydroxytryptamine 2b receptor

5-hydroxytryptamine 2c receptor

5-hydroxytryptamine 4b receptor

5-hydroxytryptamine 6 receptor

5-hydroxytryptamine 7 receptor

5-hydroxytryptamine 7b receptor

dopamine 1 receptor

dopamine 2 long receptor

dopamine 2 short receptor

dopamine 2 receptor

dopamine 3 receptor

dopamine 4 receptor

metabotropic glutamate 3 receptor

metabotropic glutamate 2 receptor

muscarinic acetylcholine receptor m1

muscarinic acetylcholine receptor m4

AN OVERVIEW OF REAXYS MEDICINAL CHEMISTRY

Search by

structure,

chemical name,

or drug name

Search by topic in citation

title, abstract, and keywords

TRANSLATING RESULTS TO RMC FOR EVALUATION

Each Schizophrenia drug can be profiled using the heat map below allowing for direct

comparison and profiling of multiple drugs vs biological targets

Clozapine

Haloperidol

Risperidone

Sertindole

Ziprazidone

Quetiapine

Olanzapine

Aprpiprazole

Palperidone

Lurazidone

Click on any cell to find

actual binding data

pIC50, pEC50, pED50, pID50, pLC50,

pLD50, pKi, pKd, pKb, pD2, pD’2,

pA2 IC50, EC50, ED50, ID50, LC50,

LD50, Ki, Kd, Kb, Ka, Ke , %

Inhibition

pX

Parameter Grinder

Log scale (7.5 is 10 fold > 6.5)

TRANSLATING RESULTS TO RMC FOR EVALUATION

Exact binding data for any compound and target can be found by clicking on an individual cell

Integration with Reaxys gives direct access to synthesis planner

Clozapine

Haloperidol

Risperidone

Sertindole

Ziprazidone

Quetiapine

Olanzapine

Aprpiprazole

Palperidone

Lurazidone

?

TRANSLATING RESULTS TO RMC FOR EVALUATION

Direct comparison of antipsychotics against the HTR6 receptor can be done to confirm our

theory that HTR6 inhibition is directly connected with improved cognition

Can we find other “off target” activity responsible for cognitive side effects of Olanzapine?

COGNITIVE EFFECTS VS DRUG TARGETS

The Disease Effect module in Pathway Studio was used to find the key regulators associated

with both Schizophrenia and cognitive disorders and impairment

COGNITIVE EFFECTS VS DRUG TARGETS

The Disease Effect module in Pathway Studio was used to find the key regulators associated

with both Schizophrenia and cognitive disorders and impairment

COGNITIVE SIDE EFFECTS AND ACETYLCHOLINE

The Disease Effect module in Pathway Studio was used to find relationships between

acetylcholine and cognitive disorders or impairment

KEY REGULATORS OF ACETYLCHOLINE

The Disease Effect module in Pathway Studio was used find all proteins responsible for the

regulation of acetylcholine. In this case, the data was limited to relationships that have at least

10 references.

TRANSLATING RESULTS TO RMC FOR EVALUATION

Using the heat map we can directly compare the activity of our antipsychotics vs. several

known regulators of acetylcholine to confirm our theory on targets involved with cognitive side

effects of antipsychotics

Clozapine

Haloperidol

Risperidone

Sertindole

Ziprazidone

Quetiapine

Olanzapine

Aprpiprazole

Palperidone

Lurazidone

SAR OF SERTINDOLE VS SELECT ANTIPSYCHOTICS

Structural analysis of antipsychotics can be done to maximize efficacy while dialing out side

effects. Careful comparison between these drugs and compounds know to affect muscarinic,

H2, and D1 receptors may lead to finding common functionality.

Sertindole

Olanzapine

Risperidone

Quetiapine

Haloperidol

CONCLUSIONS

1. Text mining is an effective method in finding relationships between

disease regulators and possible side effects

2. Known drugs and “tool” compounds can be mapped to disease

regulators uncovering relationships between drugs and side effects

3. Validation of key side effects can be found by mapping clinical data to

a drug, drug class, or therapeutic target

4. Relationships found via text mining can be validated by comparing

actual bioactivity data against multiple targets

5. Careful expansion of text-mined literature can aid in understanding

side effects at early stages in drug development and help pharma in

drug safety assessments

CREATING A PV/SAFETY SOLUTION USING LSS PRODUCTS

Embase is a biomedical search tool that searches 8400+ journals reviewed and indexed by

biomedical professionals and can be used to provide further insight to the connection between

antipsychotic drugs and cognitive side effects via a more comprehensive literature search

QUOSA Virtual Library Platform for literature sharing

Text Mining & Data Integration

In House

PDF Library

Thank you for joining our webinar today:

Reaxys Medicinal Chemistry and Pathway Studio:

Explore Drug Targets for Schizophrenia

with Jim Rinker

If you have any questions for our speaker, please type them into the

CHAT window.

If you would like more information about Reaxys Medicinal Chemistry

or Pathway Studio, please contact us at:

BDTraining@elsevier.com

Text Mining Full Text for Molecular Targets – March 31, 2015 – George Jiang