THE REAXYS CHEMISTRY
DISCOVERY ENGINE
REAXYS MEDICINAL
CHEMISTRY
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COMPLEX PROCESS- MEDICINAL CHEMISTS FOR INSTANCE NEED TO COLLECT, ORGANIZE
AND COMPARE INFORMATION FROM DIFFERENT SOURCES… THIS IS TIME CONSUMING AND
ERROR PRONE
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AND TO MAKE A DECISION ON WHICH EXPERIMENT TO DO, YOU WANT TO ORGANIZE YOUR CONTENT,
NORMALIZE AND COMPARE, TO UNDERSTAND WHICH COMPOUND INTERACTS WITH WHICH TARGET AND
TRIGGER WHICH BIOLOGICAL EFFECT—THAT'S A LOT OF MANUAL WORK!
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WHAT IS REAXYS MEDICINAL CHEMISTRY?
GOAL
‡ Enable better decisions to be made
throughout drug discovery process
‡ Better select the most promising compounds
to progress into the clinic
‡ Abandon the wrong compounds earlier
HOW
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Access millions of chemical compounds
Search biological experimental results
Thousands of druggable proteins
Intuitive user interface
Powerful underlying classification and
organisation
BECOME
‡ More effective
‡ More efficient
‡ More quickly
ACHIEVE
‡ Find and optimise a promising chemical series
‡ Explore the pharmacological effect of selected
compounds
‡ Investigate the targets with which the
compound series interacts
‡ Use for the assessment of new drugs, compound
repurposing, lead identification and lead
optimisation
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ACCESS ESSENTIAL INFORMATION
ALIGNED TO MEDICINAL CHEMISTS, PHARMACOLOGISTS AND COMPUTATIONAL CHEMISTS WORKFLOW
Compound
Chemical structure ,Name, code, synonym of compound
Druggable target
Explore Target affinity patterns of chemical compounds
In vitro and Cell Based assays
In vitro assays (binding, second messenger etc..) and Cell based assays for example : Aggregation,
Angiogenesis, Apoptosis, Cell differentiation, Cellular Cycle, Chondrogenesis
Animal models disease
ovariectomized rat in osteoporosis, treatment of glaucoma, Xenografted animals with tumors to test and
develop antineplastic drugs
Pharmacokinetic and ADME Properties
Metabolic stability, Intrinsic clearance, Half life of elimination, Bioavailability, In vivo Clearance
Toxicity
Cytotoxicity, cardiotoxicity, chronic toxicity
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RMC 2 CONTENT
Patents Origin and starting date
>80 000 Patents
‡ US : 1971-present
‡ EP : 1979-present
‡ WO : 1978-present (English only)
‡ Patents are coming from the A61K class
mainly but not only.
« The most comprehensive medicinal
chemistry solution on the market »
Articles and Journals
‡ >1000 Journals Covered
‡ >300 000 Articles
‡ From 1980 to Present
Drugable Targets
‡ >7000 Drugable Targets
‡ 4.5M Cpds
‡ 20M bioactivities
Extended Content
‡ Integrated GOSTAR data
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ESSENTIAL INFORMATION: 100+ EXPERIMENTAL FIELDS
Reaxys Medicinal Chemistry excerpts all the relevant Quantitative data
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RMC KEY FEATURES
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REAXYS MEDICINAL CHEMISTRY- INTUITIVE UI
REAXYS-LIKE MEDICINAL CHEMISTRY OPTIMIZED QUERY/HOME PAGE
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RESULTS VIEW - HEATMAP
Filters to
narrow down
Manage X and Y axis
Bioactivity
data based on
pX values
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PX CONCEPT ?
Parameter Filter
IC50,Ki,% Inhibition, %,EC50,pKi,ED50,pIC50,AUC,Emax(%),
Concentration,Cmax,nH,pA2,% Stimulation,Tmax,Fold
increase,t1/2 el,Rate,Number,KD,pEC50,pKb,IA
(%),Time,Km,ID50,Delta, Vmax,Cl,Clint,Ue (%),pD2,%
Max,Kb,Bmax,Cavg,Pressure,Amount,t1/2,
Cl/F,Cmin,MED,fu,F(%),Dose,ClR,AUC i/AUC,LD50,Frequency
PARAMETERS RELATED TO CONCENTRATION
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
Parameter Grinder
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
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REAXYS MEDICINAL CHEMISTRY
& REAXYS- INTEROPERABILITY
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REAXYS & REAXYS MEDICINAL CHEMISTRY
INTEGRATION WITH REAXYS
* illustrative prototype - actual implementation may look different
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DRUG DISCOVERY: THE DREAM TEAM!
Substance
Search
Integrated
Bioactivity Data
In Vitro Data
In Vivo Data
Competitive
Intelligence
Literature
Search
Reaction
Conditions
Synthetic
Tractability
Structure
Search
Chemistry
Biological
Profiling
Background
information
Novelty
Search
Synthetic Route
Planning
Literature
Search
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USE CASES
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ACCESS TO KNOWLEDGE ALONG DRUG DISCOVERY CHAIN
Project Kick off
‡ Indications for target
‡ Compound active on
target
‡ Most active compounds
(IC50, Ki, EC50 < 50nM)
‡ Most active competitors
‡ Target selectivity
‡ PK of Compounds classes
‡ Adverse effects : CYPblockade
‡ Adverse effect : hERGactivity
Compound Library
‡ Focused Library
‡ hERG Model
‡ CYP Model
HTS/Virtual Screening
Hit to Lead
‡ Calcium T Type Channel
‡ High affinity towards the
target
‡ Hit Generation : customer
story
‡ Show selectivity versus
targets
‡ Phenotypic in silico
Screening
‡ Reduce binding to HAS
‡ Improve cell permeability
‡ Not be metabolized
rapidly
‡ Not interfere with the
P450 enzymes
‡ Not interfere with the
Pgp
‡ Show selectivity versus
targets (Advanced)
‡ Multiple inhibitors : Renin
angiotensin pathway
Lead Optimization
‡ Exploration of structural
features of a lead series
of Compounds
‡ Safety pharmacology (off
Targets)
‡ Pharmacokinetics
‡ ADMET
‡ Computational chemistry
and molecular modeling
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Project Kick off –
AKT1 Inhibitors
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WHICH SUBSTANCES ARE THE MOST ACTIVES ON MY TARGET
(HUMAN) OF INTEREST ?
‡ Scenario (New Project)
NEW PROJECT FOCUSED ON FINDING NEW AKT1 INHIBITORS WITH LESS AFFINITY
ON AKT2 (MINIMIZING ADVERSE EFFECT)
AKT IS ASSOCIATED WITH TUMOR CELL SURVIVAL, PROLIFERATION, AND
INVASIVENESS.
THE ACTIVATION OF AKT IS ALSO ONE OF THE MOST FREQUENT ALTERATIONS
OBSERVED IN HUMAN CANCER AND TUMOR CELLS.
‡ Akt1 has been implicated as a major factor in many types of cancer
‡ Akt2 is an important signaling molecule in the Insulin signaling pathway
‡ The role of Akt3 is less clear, though it appears to be predominantly
expressed in the brain
Search for active chemotypes on AKT1?
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SEARCH FOR ACTIVE CHEMOTYPES ON AKT1?
Simple Target
name search
returns all results
All compounds
tested on Akt1
Targets on which
AKT1 inhibitors
were also tested on
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SEARCH FOR ACTIVE CHEMOTYPES ON AKT1?
HUMAN SPECIES
Retrieve compounds
tested on human AKT1
Compounds tested on
Human AKT1 are also
tested on AKT2, AKT3
ERK2 and PDK1
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SEARCH FOR ACTIVE CHEMOTYPES ON AKT1?
VERY ACTIVE COMPOUNDS
Answers
16 compounds and
18 experimental data
Filter on very active
compound pX>=9
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Hit to lead –
caspase-based
apoptosis
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WHAT IS KNOWN ABOUT MY SUBSTANCE OF INTEREST?
Scenario
An Apoptosis inducer ‘chemotype’ from a cell- and caspase-based apoptosis
high-throughput screening was found (Compound 1). A structure activity
relationship expansion lead to compound 2 (Schema1)
Compound 1
Compound 2
HTS hit
SAR expansion
COC1=CC=C(C=C1)N(C)C1=NC(Cl)=NC2=C1C=CC=C2
What is known about this chemotype/template
(Compound 2) in Reaxys Medicinal Chemistry?
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WHICH ARE THE KNOWN ACTIVITIES OF MY CHEMOTYPE ON
OTHER TARGET CLASSES ?
Scenario
(Hit to
lead)
An Apoptosis inducer ‘chemotype’ from a cell- and caspase-based apoptosis
high-throughput screening was found (Compound 1). A structure activity
relationship expansion lead to compound 2 (Schema1)
Compound 1
Compound 2
HTS hit
SAR expansion
COC1=CC=C(C=C1)N(C)C1=NC(Cl)=NC2=C1C=CC=C2
Which are the known activities of my Chemotype on
other target classes in Reaxys Medicinal Chemistry?
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THANK YOU
ANY QUESTIONS?
DR CHARLES MARTINEZ
SOLUTION SALES MANAGER
TEL: +447769301845
EMAIL: [email protected]
TECHNICAL [email protected]
JOIN THE BETA
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EXTRA SLIDES
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RESULTS VIEW - HEATMAP
Filters to
narrow down
Manage X and Y axis
Bioactivity
data based on
pX values
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PX CONCEPT ?
Parameter Filter
IC50,Ki,% Inhibition, %,EC50,pKi,ED50,pIC50,AUC,Emax(%),
Concentration,Cmax,nH,pA2,% Stimulation,Tmax,Fold
increase,t1/2 el,Rate,Number,KD,pEC50,pKb,IA
(%),Time,Km,ID50,Delta, Vmax,Cl,Clint,Ue (%),pD2,%
Max,Kb,Bmax,Cavg,Pressure,Amount,t1/2,
Cl/F,Cmin,MED,fu,F(%),Dose,ClR,AUC i/AUC,LD50,Frequency
PARAMETERS RELATED TO CONCENTRATION
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
Parameter Grinder
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
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PX CONCEPT COMPETITIVE ADVANTAGE
pX it’s a unique way of quantifying affinity of compounds on targets, cells line etc….
‡ Allow user to better compare biological results across publications (articles and Patents)
and bioassays.
‡ Key component for patent where affinities are most of the time display as ranges and
very difficult to compare.
‡ Insure end users to encompass all the affinity data that they are searching for without
being an expert (knowing all the parameters and units used in publications)
‡ Facilitate analysis using third party tools (Spotfire, Pipeline Pilot) through the export.
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HOW THE PX IS CALCULATED ? : AFFINITY RESULTS
Results are expressed as –log10 (affinity) using pIC50, pEC50, pED50, pID50,
pLC50, pLD50, pKi, pKd, pKb, pD2, pD’2, pA2
Æ pX = parameter Value
Results are expressed as affinity using IC50, EC50, ED50, ID50, LC50,
LD50, Ki, Kd, Kb, Ka, Ke
ÆpX=
-log10(parameter value)
Remark
If values are expressed in non molar units, they are first converted in M (using
molecular weight, animal/tissue weight or volume)
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HOW THE PX IS CALCULATED ? : % INHIBITION
Results are expressed as % Inhibition
- Concentration of the compound is not Available
ÆpX is not calculated
- Concentration of the compound is Available as :
Æ pX is not calculated
- RangesÆ
- Single value Æ pX is calculated :
- Assuming the compound could achieve a 100% inhibition
-Assuming the slope (Hill coeff) = 1
-If
%Inhibition > 25
ÆpX
= -log10(IC50)
- If %Inhibition < 25 ÆpX = 1
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REAXYS MEDICINAL CHEMISTRY THE REAXYS CHEMISTRY DISCOVERY ENGINE