Reaxys Medicinal Chemistry

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INTRODUCTION TO REAXYS MEDICINAL CHEMISTRY

Olivier Barberan

Senior Product Manager

Elsevier

October 16, 2013

Your Presenter: Dr. Olivier Barberan

Webinar presented October 16, 2013

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SITUATION: DRUG DISCOVERY

ELN

Biology

Therapeutic target

Chemistry

Check chemical feasibility

Synthesize or buy

Test

Check ADME/Tox

Report

Analyze SAR

Generate chemistry ideas

In-house

Knowledge survey

ELN

DBs

Flatfiles

Journals

Journals

Docs

Known ligands

No single solution will fit all needs, but…

DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

http://www.rcsb.org/pdb

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Therapeutic target

Check chemical feasibility

Synthesize or buy

Test

Check ADME/Tox

Report

Analyze SAR

Generate chemistry ideas

Knowledge survey

Chemistry

In-house

ELNKnown ligands

Flatfiles

Docs

Biology

… is that really necessary?Hows about interoperability and

integration?

Wouldn’t it be nice being able to switch seamlessly between

scientific domains and find data that you have not even thought about, but would be important?

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AGENDA

Elsevier Life science Solution

Reaxys Medicinal Chemistry

Content coverage

Application in Drug discovery

QA


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TARGETINSIGHTS

PHARMAPENDIUM

EMBASE QUOSA

PATHWAY STUDIO

A SUITE OF INTEROPERABLE, DOMAIN-SPECIFIC, DECISION SUPPORT TOOLSPART OF LIFE SCIENCE SOLUTIONS

TEXT MINING MEDSCAN

TAXONOMIES

(CONTENT) INTEGRATI

ON


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MEDSCAN

TAXONOMIES

(CONTENT) INTEGRATI

ON

TARGETINSIGHTS

PHARMAPENDIUM

EMBASE QUOSA

PATHWAY STUDIO

REAXYS CHEMISTRY DISCOVERY ENGINE

Combines relevant chemistry information from 16,000 periodicals and over 500m experimentally validated facts with synthesis planning functionality.

REAXYS MEDICINAL CHEMISTRY

Identify, optimize and prioritize compounds with optimum affinity, selectivity and ADMET properties.

A SUITE OF INTEROPERABLE, DOMAIN-SPECIFIC, DECISION SUPPORT TOOLSPART OF LIFE SCIENCE SOLUTIONS


CONTENT COVERAGE

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ESSENTIAL INFORMATION: 100+ EXPERIMENTAL FIELDS

Reaxys Medicinal Chemistry excerpts all the relevant Quantitative data


ESSENTIAL INFORMATION: SUPPORTING CRITICAL STAGES

IN THE DRUG DISCOVERY & DEVELOPMENT PIPELINE

9DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

COMPUTATIONAL CHEMIST (CADD*)

“I need to find hits for druggable targets” (virtual screening)

MEDICINAL CHEMIST

“I need to optimize chemical structures in order to improve affinity, selectivity ADMET properties and decrease side effects”

HIT TO LEAD

PHARMACOLOGIST

“I need to define relevant pharmacological models on animals”

LEADOPTIMIZATION

PRECLINICAL DEVELOPMENT


“I need to optimize other pharmaceutical properties while maintaining affinity” (QSPR)

SYNTHETIC CHEMIST

“I need to define the easiest and most productive way to reach my target compound”

PROJECT MANAGER

“I need to be up to date with regards to competitors working on the same subjects” (Which compounds, targets are published in Journals and/or patents)


“I need to optimize affinity and selectivity of hits” (Structure based design QSAR)

DISCOVERY

ESSENTIAL INFORMATION

• 2.4 M chemical compounds• 9 M biological experimental

results• 5100 Pharmacological targets

THE WORLD OF MEDICINAL CHEMISTRY AT YOUR FINGERTIPS

10DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

REAXYS MEDICINAL CHEMISTRY:THE MOST POWERFUL AND VERSATILE MEDICINAL CHEMISTRY DISCOVERY ENGINE

RELEVANT ANSWERS

• Chemistry driven searches(Substructure/Similarity)

• Pharmacology driven searches (Target, Cell, Bioassay)

• Taxonomies-driven searches

ACTIONABLE

• Intuitive and powerful user-interface

• No access barrier• Flexible export

(Manageable by user)

REAXYS MEDICINAL CHEMISTRY : PATENTS COVERAGE

Patents Origin and starting date

US : 1971-present EP : 1979-presentWO : 1978-present (English only)

Patents are coming from the A61K class mainly but not only.

Patents count : 50632


REAXYS MEDICINAL CHEMISTRY : JOURNALS COVERAGE

206421 articles are included in Reaxys Medicinal Chemistry

corresponding to 1047 Journals from 1980 to present.

Some articles stored in Reaxys Medicinal Chemistry are older than 1980. 1000 articles spread between 1979 and 1941.


ESSENTIAL INFORMATION

COMPOUND CHEMICAL STRUCTURE ,NAME, CODE, SYNONYM OF COMPOUND

DRUGGABLE TARGETEXPLORE 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 PROPERTIESMETABOLIC STABILITY, INTRINSIC CLEARANCE, HALF LIFE OF ELIMINATION, BIOAVAILABILITY, IN VIVO CLEARANCE

TOXICITYCYTOTOXICITY, CARDIOTOXICITY, CHRONIC TOXICITY


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INTERACT WITH YOUR WORKFLOW


Link to full text articles

Export data in multiple formats: Text, Excel, SDF, RDF, XML files to be incorporated into third party tools

Link to Reaxys:‐ Compounds‐ Citations

Link to Embase

Link to Drug Bank

Link to Protein 3D structure: PDB

Link to Uniprot

Link to full text Patent: Espacenet

APPLICATION IN DRUG DISCOVERY

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Project Kick off

Compound Library

HTS/Virtual Screening Hit to Lead

Lead Optimizatio

n

ACCESS TO KNOWLEDGE ALONG DRUG DISCOVERY CHAIN

- Focused Library- hERG Model- CYP Model

- 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 : CYP-blockade- Adverse effect : hERG-activity

- Calcium T Type Channel- Hit Generation : customer story- Phenotypic in silico Screening

- High affinity towards the target - Show selectivity versus targets- Reduce binding to HSA- 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

- Exploration of structural features of a lead series of Compounds-Safety pharmacology (off Targets) - Pharmacokinetics- ADMET - Computational chemistry and molecular modeling

PROJECT KICK OFF

AKT1 INHIBITORS

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AKT INHIBITORS

• 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

THEREFORE, UNDERSTANDING AKT AND ITS PATHWAYS IS IMPORTANT FOR THE CREATION OF BETTER THERAPIES TO TREAT CANCER AND TUMOR CELLS.


ABOUT AKT1 INHIBITORS IN REAXYS MEDICINAL CHEMISTRY

• MOST ACTIVE COMPOUNDS ON AKT1 (IC50, KI OR KD BELOW 0.05 ΜM?)

• TARGET SELECTIVITY (AKT1 VERSUS AKT2)

• PK OF COMPOUNDS CLASSES

• ADVERSE EFFECTS : CYP-BLOCKADE

• ADVERSE EFFECT : HERG-ACTIVITY


PROJECT KICK OFF

LIVE DEMO

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IN SUMMARY

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• Reaxys Medicinal Chemistry is a Powerful solutions across the entire Drug Discovery Workflow

• Designed to help Medicinal and Computational Chemists in all sectors, advance more quickly and confidently through their research.

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THANK YOU

QUESTIONS?

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CLIQUEZ ICI POUR CHANGER LE TEXTE

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THANK YOU

FOR MORE INFORMATION AND QUESTIONS PLEASE USE THE CONTACT DETAILS ON OUR ONLINE PAGE.

OUR NEXT REAXYS WEBINAR IS ON OCTOBER 22. AND YOU MAY ALSO BE INTERESTED IN JOINING OUR REAXYS WEBINARS. ALL WEBINARS MAY BE FOUND ON OUR WEBINAR PAGE

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http://www.elsevier.com/online-tools/reaxys/reaxys-medicinal-chemistry

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Transcript of Reaxys Medicinal Chemistry