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Reaxys Medicinal Chemistry: An introduction - webinar September 18 2013
 

Reaxys Medicinal Chemistry: An introduction - webinar September 18 2013

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Dr. Olivier Barberan introduced us to the main features and benefits of using our medicinal chemistry database.

Dr. Olivier Barberan introduced us to the main features and benefits of using our medicinal chemistry database.

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    Reaxys Medicinal Chemistry: An introduction - webinar September 18 2013 Reaxys Medicinal Chemistry: An introduction - webinar September 18 2013 Presentation Transcript

    • REAXYS MEDICINAL CHEMISTRY DR. OLIVIER BARBERAN ELSEVIER SEPTEMBER 2013 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER 1
    • 2 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
    • 3 Therapeutic target Check chemical feasibility Synthesize or buy Test Check ADME/Tox Report Analyze SAR Generate chemistry ideas Knowledge survey Chemistry In-house ELN Known 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?
    • AGENDA Elsevier Life science Solution Reaxys Medicinal Chemistry Content coverage Application in Drug discovery QA 4 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • TARGETINSIGHTS PHARMAPENDIUM EMBASE QUOSA PATHWAY STUDIO A SUITE OF INTEROPERABLE, DOMAIN-SPECIFIC, DECISION SUPPORT TOOLS PART OF LIFE SCIENCE SOLUTIONS 5 TEXT MINING MEDSCAN TAXONOMIES (CONTENT) INTEGRATION DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • MEDSCAN TAXONOMIES (CONTENT) INTEGRATION 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 TOOLS PART OF LIFE SCIENCE SOLUTIONS 6 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • CONTENT COVERAGE 7 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • ESSENTIAL INFORMATION: 100+ EXPERIMENTAL FIELDS Reaxys Medicinal Chemistry excerpts all the relevant Quantitative data DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • ESSENTIAL INFORMATION: SUPPORTING CRITICAL STAGES IN THE DRUG DISCOVERY & DEVELOPMENT PIPELINE 9 DR. 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” LEAD OPTIMIZATION PRECLINICAL DEVELOPMENT COMPUTATIONAL CHEMIST (CADD*) “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) COMPUTATIONAL CHEMIST (CADD*) “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 10 DR. 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-present WO : 1978-present (English only) Patents are coming from the A61K class mainly but not only. Patents count : 50632 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • 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. DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • ESSENTIAL INFORMATION 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 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • INTERACT WITH YOUR WORKFLOW 14 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER 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 15 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER 16 Project Kick off Compound Library HTS/Virtual Screening Hit to Lead Lead Optimization 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 17 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • 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. DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • 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 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • PROJECT KICK OFF LIVE DEMO 20 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • IN SUMMARY 21 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER • 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.
    • 22 THANK YOU QUESTIONS? 22 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • 23 BACKUP SLIDES 23 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • HIT GENERATION : LIGAND VIRTUAL SCREENING CALCIUM T TYPE CHANNEL 24 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • LIGAND BASED VIRTUAL SCREENING : USING REAXYS MEDICINAL CHEMISTRY 01/10/201 3 25 LABORATOIRES PIERRE FABRE 01 JUL 2011 • OBJECTIVE DESCRIBE AN IN SILICO SCREENING APPROACH USING REAXYS MEDICINAL CHEMISTRY • CASE STUDY ON T-TYPE CALCIUM CHANNELS DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • 01/10/201 3 26 LABORATOIRES PIERRE FABRE 01 JUL 2011 LEADS Hits To-Leads In-Silico Screening Profiling and Qualifying Leads Heat map approach Pharmacology Profile Efficacy Selectivity Off Targets HITS TO LEADS In Silico scrrening DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • LIGAND-BASED IN SILICO SCREENING DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER Target Synonyms are searchable Simple selection of parameters in the list ANSWERS 130 compounds and 1200 experimental data Simple Target name search returns all results Bioassays Name Search
    • 01/10/201 3 28 Representation & Chemical Space Molecular descriptors & Fingerprints Virtual Screening Pharmacophoric Similarity N O N N N O N N N 314 Hits Diversity DB 130 Query structures 1. Molecular diversity and chemical originality 2. Compounds availability 39 compounds ordered for testing LIGAND-BASED IN SILICO SCREENING "Drug-like" Filtering DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
    • 01/10/201 3 29 Electrophysiology experiments : Screening @10 µM on Cav3.2 T-Type channels 9 compounds with a % inhibition > 75% 15 compounds with a % Inhibition >50% LABORATOIRES PIERRE FABRE 01 JUL 2011 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 29 30 31 32 33 34 35 36 37 38 39 0 25 50 75 100 Compound # (@ 10µM) Peakcurrentinhibition(%) 28 BIOLOGICAL ACTIVITY
    • CHEMICAL STRUCTURE OF ACTIVE COMPOUNDS 30 Compound 18 Compound 14 Compound 20 Compound 37 Compound 35 Compound 8 Compound 17 Compound 30 Compound 32 DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER