Drug discovery expert, Jim Rinker, will discuss the process for exploring drug targets for schizophrenia using the tools in Elsevier's R&D portfolio. This approach features a specific workflow between Reaxys Medicinal Chemistry and Pathway Studio. Beginning with mapping known schizophrenia drugs to regulators, Mr. Rinker will walk through the keys steps in finding the proper drug used to improve cognitive function. This step-by-step method of research and data extraction will demonstrate how using these platforms can help identify side effects, build a consensus model, properly profile drugs and effectively map cognition.

1. USING ELSEVIER’S
LIFE SCIENCE
SOLUTION PORTFOLIO
IN EXPLORING DRUG
TARGETS FOR
SCHIZOPHRENIA
Jim Rinker
Customer Consultant
Elsevier
6/30/15

2. Check chemical
feasibility
Synthesize
or buy
Test
Check
ADME/Tox
Report
Analyze
SAR
Chemistry
In-house
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

3. UNDERSTANDING DISEASE TARGETS AND INHIBITORS
Cell
Process
Disease
Target
Small
Molecule
Side EffectScaffold
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

4. 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

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. CONSENSUS REGULATORS
Mapping of antipsychotic drugs to regulators reveals two distinct classes
Dopamine Serotonin

15. 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

16. 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

17. 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.

18. 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.

19. 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.

20. 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.

21. 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

22. COGNITIVE SIDE EFFECTS VS TARGET MODULATION
Multiple serotonin and dopamine receptors have a direct effect on cognition

23. COGNITIVE EFFECTS OF ANTIPSYCHOTIC DRUGS

24. 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

25. 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

26. 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

27. USING PHARMAPENDIUM TO FIND REPORTED ADVERSE EVENTS
An example of adverse event data found on cognitive disturbance for the antipsychotic drug

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. AN OVERVIEW OF REAXYS MEDICINAL CHEMISTRY
Search by
structure,
chemical name,
or drug name
Search by topic in citation
title, abstract, and keywords

39. 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)

40. 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

41. 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?

42. 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

43. 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

44. COGNITIVE SIDE EFFECTS AND ACETYLCHOLINE
The Disease Effect module in Pathway Studio was used to find relationships between
acetylcholine and cognitive disorders or impairment

45. 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.

46. 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

47. 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

48. 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

49. 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

50. 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
TextMining Full TextforMolecular Targets – March 31,2015 –George Jiang