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Published by: SMI Publishing, Ltd
Published: May. 16, 2007
Table of Contents
- Day One
- 8.30 Registration & Coffee
- 9.00 Chairman's Opening Remarks
- Dr Alexander Hillisch, Director, Medicinal Chemistry & Head, Computational Chemistry, Bayer HealthCare.
- 9.10 CAN WE PREDICT ADMET PROPERTIES OF COMPOUNDS FROM PROTEIN STRUCTURE?
- Dr Alexander Hillisch, Director, Medicinal Chemistry & Head, Computational Chemistry, Bayer HealthCare.
- 9.30 STRUCTURAL AND MUTAGENESIS STUDIES ON CYTOCHROME P450 2D6
- Implications on the prediction of substrates and inhibitors
- Crystal structure of CYP2D6 shows classic P450 fold and key residues in active site
- Docking and SDM studies show differing roles for asp_301 and glu_216. Phenylalanine’s 120 and 483 have key binding roles whereas phe_481 is a recognition residue
- Debrisoquine oxidation involves multiple mechanisms
- Metabolite prediction requires knowledge of substrate site reactivity and accessibility as well as docking to active site
- Inhibition can occur in multiple sites often remote from haem group
- Dr Frank E. Blaney, Research Manager, Computational & Structural Chemistry, GlaxoSmithKline.
- 10.10 CYP450S INHIBITION: STRUCTURAL, PRACTICAL APPLICATIONS TO DRUG DISCOVERY
- Exploiting structural information to maximise drug safety
- Cyp450s inhibition: challenges and opportunities
- Structural plasticity: why bother?
- How to design out Cyp450 inhibition
- Real life applications
- Cyp450s inhibition: lessons learned
- Dr Fabrizio Giordanetto, Associate Principal Scientist, AstraZeneca.
- 10.50 Morning Coffee
- 11.20 AUTOMATED DOCKING AND VIRTUAL SCREENING OF CYTOCHROMES P450'S AS A TOOL FOR COMPOUND SELECTION
- Modelling guided site directed mutagenesis of Cyt P450 2D6
- Role of water molecules in automated docking strategies in Cyt P450s and Kinases
- Catalytic site prediction and virtual screening of Cyt P450 2D6 substrates
- Cyt P450 2D6 - ligand interactions: in silico predictions and experimental validations
- Cyt P450 2D6 homology models and crystalstructure comparisons
- Nico Vermeulen, Scientific Director LACDR-Amsterdam & Head Section, Molecular Toxicology, Vrije Universiteit.
- 12.00 CYPSCORE
- A quantum chemical approach for the prediction of likely sites of p450-mediated metabolism
- CypScore is a tool for the prediction of Cytochrome P450-mediated metabolism
- Based on quantum-chemically derived atom descriptors and regression models
- Models for all major phase-I oxidation reactions
- In-house application for guiding compound optimization to improve metabolic stability
- Application examples on published metabolic data are presented
- Dr Andreas H. Göller , Senior Scientist, Chemical Research, Bayer.
- 12.40 Networking Lunch
- 1.50 SYGMA
- Combining expert knowledge and empirical scoring to predict drug metabolites
- Rule-based metabolite prediction: ranking by empirical probability score identifies most likely metabolites
- Application within Organon: support of analytical metabolite identification and medicinal chemistry
- Reaction fingerprints enabled systematic analysis of large metabolite databases
- Metabolic reaction rules were evaluated and refined based on performance on the training database
- Evaluation based on independent dataset demonstrated the predictive value of this approach
- Dr Lars Ridder, Research Scientist, Organon NV.
- 2.30 PREDICTING METABOLIC STABILITY
- Training and Retraining of a Gaussian Process Model
- Numerical prediction versus classification
- Introduction into Gaussian Processes (GP)
- Novel data expanding the model validity
- Workflow integration and application examples
- Anton Schwaighofer, Research Scientist, Fraunhofer FIRST.
- 3.10 Afternoon Tea
- 3.40 MOLECULAR MODELLING-ASSISTED ATTENUATION OF UNDESIRABLE PXR ACTIVITY
- Understanding the structure-activity relationship of PXR activators
- Hypothesis of human PXR activation
- Docking, rationale, and designs to test the hypothesis
- Pharmacophore elements of human PXR agonists
- Reducing PXR activity by disrupting key structural elements in the receptor
- Examples
- Dr Maricel Torrent, Research Fellow, Medicinal Chemistry, Merck .
- 4.20 THE JOURNEY OF DRUG DISCOVERY TO DRUG DESIGN
- How far have we travelled?
- Dr Matthew Segall, Senior Director ADMET, BioFocus DPI.
- 5.00 Chairman’s Closing Remarks and Close of Day One
- Day Two
- 8.30 Registration & Coffee
- 9.00 Chairman's Opening Remarks
- Dr Alexander Hillisch, Director, Medicinal Chemistry & Head, Computational Chemistry, Bayer HealthCare.
- 9.10 SPECIAL ADDRESS
- IN SILICO SCREENS AND TOOLS FOR DRUG DISCOVERY
- Drug discovery/development process
- Routinely conducted assays (drug disposition)
- Need for in silico approaches
- In silico screens and models
- Designing molecules in silico
- Vijay Gombar, Research Advisor, Drug Deposition, Eli Lilly & Co.
- 9.50 NEXT GENERATION DOCKING & HOMOLOGY MODELLING APPROACHES APPLIED TO ADMET RELEVANT PROTEINS
- Richard Friesner, Professor of Chemistry, Columbia University & Co-Founder, Schrodinger.
- 10.30 Morning Coffee
- 10.50 EARLY TOXICITY ASSESSMENT FOR LEAD DISCOVERY
- Optimizing the Use of Prediction Software
- in silico toxicology in lead discovery
- Theoretical study on the necessity to integrate predictions tools
- Case studies: prediction of mutagenicity and carcinogenicity
- Future directions
- Cedric Merlot, Cheminformatics Scientist, Scientific Computing, Serono.
- 11.40 MODELLING OF DRUG-TRANSPORTER INTERACTIONS USING STRUCTURAL INFORMATION
- Relevance of general and specific models in drug discovery
- Lately, the importance of drug transporter proteins for both absorption, distribution, including distribution across the blood brain barrier, and elimination has been established. The most known is the ABC transporter P-glycoprotein (ABCB1), but others, like MRP2 (ABCC2) or BCRP (ABCG2), have also shown to be of great consequence for both absorption and elimination of drug compounds.
- No crystal structures for human ABC transporters are available so far. Homology models have been developed for P-glycoprotein based on bacterial ABC transporters and give some hints on what kind of interactions may be possible. The picture is rather more complicated due to the fact that several binding sites have been idenitifed P-glycoprotein.
- Models based on the substrates alone, pharmacophore models, require the knowledge which transporter and, if applicable, which binding site is relevant. Using closely related compounds it may be assumed that they interact reasonably similar with the transporter system. However, such a model cannot be used generally.
- A general model needs transporter specific interaction data obtained in equivalent experiments for a diverse set of compounds. Problems associated with such data and subsequent modelling efforts will be discussed.
- Within drug discovery general models are applicable in the early phase. In later phases specific models for a given compound series may be more appropriate to improve the properties of compounds within that series. However, structural information will in all phases help to understand the transporter interaction and thereby also help to improve the property in question.
- Dr Susanne Winiwarter, Senior Research Scientist, AstraZeneca.
- 12.20 Networking Lunch
- 12.30 IN SILICO COMPOUND PROFILING METHOD FOR P-GLYCOPTROTIEN MEDIATED EFFLUX
- Significance analysis of pharmacophores to identify chemical structure markers in P-gp substrates
- We have developed a pharmacophore-based predictive model to differentiate P-gp substrate from non Substrate
- We used significance analysis and decision tree algorithms to identify key pharmacophore markers
- We used a diverse set of known drugs as training and test set
- The predictive success rate of the model in test set is >90%
- We have applied this method at Amgen in some lead optimization projects
- Summary of results
- Dr Mario Cardozo, Principal Scientist, Computer Assisted Drug Discovery, Amgen.
- 2.10 ROLE OF STRUCTURAL MODELS OF P-GLYCOPROTEIN
- The prediction of actively transported small molecules
- Structural information available
- Protein homology models - how reliable are they?
- Biochemical information - linking structure to function
- The molecular basis of polyspecificity
- Gerhard Ecker, Associate Professor, University Of Vienna.
- 2.50 COMPOUND PROFILING FOR PGP & BCRP SUBSTRATES
- What are the similarities and differences between PgP and BCRP substrates?
- 3D pharmacophore models
- Classification models
- Computed properties
- Application to drug discovery
- Dr Pil H. Lee, Principal Scientist, Computer Assisted Drug Discovery, Pfizer .
- 3.30 Afternoon Tea
- 3.50 CRYSTALLOGRAPHIC ANALYSIS OF DRUG BINDING TO HUMAN SERUM ALBIUM
- An ADMET trouble-maker
- Stephen Curry, Reader in Structural Biology, Imperial College London.
- 4.30 REDUCING DRUG-BINDING TO HUMAN SERUM ALBUMIN
- A Structural and Computational Approach
- NMR-based studies of molecules bound to domain 3 of human serum albumin
- Computational analysis of substituents which reduce compound binding to human serum albumin
- Andrew Petros, Associate Research Fellow, Abbott Laboratories.
- 5.00 Chairman’s Closing Remarks and Close of Day Two
AbstractThe number of x-ray structures of proteins relevant for ADMET properties of drug molecules has increased remarkably during the last few years. In addition improved QSAR and homology modelling techniques have contributed to an understanding of processes involved in ADMET at molecular detail.
SMi’s In Silico ADMET conference will bring together structural biologists, computational chemists, physicochemists from pharmaceutical and biotech industry and academia to discuss the current state of ADMET prediction. This timely topic involves a comparison of different computational chemistry approaches (QSAR, QSPR and protein structure-based design). Furthermore our international panel of speakers will examine the progress in the field of homology modelling and its utility in drug design.
Our exceptional speaker panel includes:
- Dr Pil H. Lee, Principal Scientist, Computer Assisted Drug Discovery, Pfizer
- Dr Frank E. Blaney, Research Manager, Computational & Structural Chemistry, GlaxoSmithKline
- Dr Susanne Winiwarter, Senior Research Scientist, DxDMPK, AstraZeneca
- Fabrizio Giordanetto, Associate Principal Scientist, Lead Generation, AstraZeneca
- Dr Maricel Torrent, Research Fellow, Medicinal Chemistry, Merck
- Dr Andrew M. Petros, Associate Research Fellow, Structural Biology, Abbott Laboratories
- Dr Mario Cardiozo, Principal Scientist, Molecular Structure, Amgen
- Dr Andreas H. Göller, Senior Scientist, Chemical Research, Bayer HealthCare
- Dr. Lars Ridder, Research Scientist, Molecular Design & Informatics, Organon
- Richard Friesner, Schrödinger Inc
- Cedric Merlot, Cheminformatics Scientist, Scientific Computing, Serono
- Dr Anton Schwaighofer, Research Scientist, Fraunhofer FIRST
- Dr. Stephen Curry, Biophysics Section, Blackett Laboratory, Imperial College London
- Ismael Zamora, Associated Professor, Pompeu Fabra University
- Gerhard Ecker, Department of Pharmaceutical Chemistry, University of Vienna
The conference will be chaired by:
Dr. Alexander Hillisch, Director, Medicinal Chemistry, Bayer HealthCare
Benefits of Attending In Silico ADMET 2007:
- COMPARE: differing approaches to computational chemistry
- DISCOVER: improved QSAR and homology modelling techniques
- UNDERSTAND: The processes involved in ADMET at molecular detail
- EXAMINE: progress made in the field of homology modelling and its utility in drug design
- IDENTIFY: future developments in protein-structure based approaches
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