Accelrys Life Sciences Symposium



Benoît Grellier, Bioinformatician,Transgene
Presentation Title: In silico epitope mapping of the human CD115 monoclonal antibody H27K15: from computer models to a new transgenic mouse model.

Abstract: The humanized monoclonal antibody H27K15 developed by Transgene specifically targets human CD115, a type III tyrosine kinase receptor involved in multiple cancers and inflammatory diseases. The identification and characterization of the epitope were successfully achieved using both homology modeling and protein-protein docking programs from Discovery Studio (Accelrys Inc.) in combination with experimental data from enzyme-linked immunosorbent assays, nuclear magnetic resonance spectroscopy and quartz crystal microbalance affinity measurements. The resulting information led to the design of a chimeric CD115 molecule carrying the human epitope of H27K15 in a murine backbone while preserving the ability to bind the murine CSF-1 and IL-34 ligands. These results provide new opportunities to minutely study the activity of H27K15 in a transgenic mouse that would express this chimeric molecule.

Francine Acher, Research Director, CNRS
Presentation Title: Molecular determinants of agonist selectivity in glutamate-gated chloride channels

Abstract: Rapid synaptic transmission in the nervous system is mediated by a very large and diverse family of ligand-gated ion channels (LGICs). One major group of LGICs are of pentameric structure, and are characterized by a highly conserved cysteine loop that is found in the extracellular N-terminal domain. These have been named "cys-loop receptors". They are activated by many different neurotransmitters such as Ach, GABA, glycine, serotonin, glutamate, histamine and dopamine. Some of these LGICs contain an additional cys-loop in the N-terminal domain. These 2-cys loop LGICs are anionic. The glycine receptor is the best known example of the 2-cys loop receptors, and the only vertebrate one. Two invertebrate 2-cys loop glutamate-gated chloride channels (GluClR's) from nematodes and arthropods (Aplysia) have been characterized. The former is only gated by glutamate whereas the latter may also be activated by GABA, b-alanine and taurine.
The recent crystallization of the GluClR from C. elegans revealed the binding pocket of the nematode receptor. An alignment of the protein sequences of the nematode and molluscan GluClR's showed that the Aplysia receptor does not contain all of the residues defining the binding mode of the nematode receptor. We built a homology model of the Aplysia receptor docked with glutamate. The comparison with the nematode X-ray structure and site directed mutagenesis investigations revealed a set of residues that determines the GluClR selectivity. These results add to the gating mechanism that was recently proposed by Calimet et al .

Thierry Convard , Head of Molecular Modeling Senior, IDENIX Pharmaceuticals Inc.
Presentation Title: Molecular dynamic simulations: helping to understand loss of nucleotides activity in HCV polymerase

Abstract: Hepatitis C virus is a Flaviviridae virus whose genome comprises a single-stranded RNA segment encoding for a single polyprotein that will be post-processed into 10 final proteins. One of the non-structural proteins is the RNA-dependant RNA polymerase that allows the replication of the viral genome. Many compounds can inhibit this polymerase in different allosteric positions; these are non-nucleosidinhibitors. Others can directly interact in the active site of the polymerase. In this category, nucleoside inhibitors are very promising because they have the capability to be a chain terminator, meaning they are incorporated into the viral genome and prematurely end the viral replication. Mutant selection is a consequence of many antiviral compounds. Consequently, it’s interesting to understand the loss of activity of a compound active in the wild type virus, which becomes inactive against a specific mutant. Can molecular dynamic simulations give us some understanding of the behavior of a compound in the wild type compared to the mutant polymerase’s virus if the fold change in activity is of 2 orders of magnitude?

Bojana Popovic, Senior Research Scientist, MedImmune
Presentation Title: Antibody Engineering Beyond Affinity Alone

Abstract: During drug development monoclonal antibodies must fulfil high standards with regard to their binding affinity, target specificity, and functional activity. It is therefore essential to develop a therapeutic antibody that not only demonstrates the required pharmacology but also displays appropriate biophysical properties.
In this talk we describe the computational and experimental approaches used to isolate high affinity monoclonal antibody, MEDI-1912. As a consequence of the mutations introduced during affinity maturation MEDI-1912 displayed an increase propensity to aggregate. Using an in silico spatial aggregation propensity tool we identified surface exposed hydrophobic amino acids responsible for aggregation that were mutated resulting in a stable antibody without compromising potency or affinity for NGF.

Rob Brown, Senior Director of Life Sciences Marketing, Accelrys
Presentation title: Accelrys Informatics Strategy and Roadmap

Abstract: Significant changes have occurred in the last few years in Life Sciences Research including the move to a balanced portfolio between biologics and small molecules, as well as the increase in collaborative research across multiple companies, CROs and academic institutions. At the same time significant changes have been occurring in the technology landscape with the increased importance of cloud computing, mobility, social collaboration and the application of big data analytics.
Accelrys has developed a new informatics suite harnessing these new technologies to address the new kinds of research challenge. In this talk we will discuss the strategy that we have developed, describe the current informatics suite and provide a roadmap for our future development. Products covered in this talk will include Insight, Chemical and Biological Registration, Accelrys ELN and Notebook, Science Cloud and Pipeline Pilot.

Arnaud Boizard, IS Service Leader, Sanofi
Presentation Title: SHERPA - A Sanofi R&D Service to Support Drug Discovery Data Exchange with External Partners

Abstract: In July 2012 the SHERPA project was launched. This project had the objective of fostering open innovation at Sanofi-Aventis R&D. Leveraging Accelrys ScienceCloud platform and Pipeline Pilot, this service aims at supporting scientific project teams which have collaborations with external partners (CROs, universities).
Pharma Research is about generating huge volume of data in chemistry, biology, etc. and scientists become engaged in complex time consuming data management activities (which induce a high risk of errors) rather than focusing on Research and analysis activities. Streamlining data exchange (ScienceCloud platform, guidelines) with external partners, SHERPA considerably reduces the time spent by the scientists (including partner) to collect and share data while guaranteeing a secure and high quality level of data.
SHERPA was honored with the first Scientific Innovation Lifecycle Leaders Award in 2013.
This talk will present the service framework (people, processes, tools) and the alignment of this Service with the Sanofi R&D strategy (project-centricity orientation and social network).

Luc Spitzer, IT Data Manager, Inventiva
Presentation Title: Gemsight – Integration of Accelrys Insight into Inventiva

Abstract: Inventiva SAS is a drug discovery company dealing with multiple clients and projects. In order to  meet our current needs, ensure flexible and stable reporting to clients, we enhanced our reporting portfolio by migrating to Accelrys Insight. One of the major criteria for selecting Insight is that it allows us to leverage on the powerful capabilities present in the underlying Pipeline Pilot tool set. We focused our development efforts in order to deliver both a stable project reporting tool and still provide an easy-to-use and flexible tool for scientist’s daily tasks such as:
-Flexible display and mining of dose-response curves
-SAR analysis
-Data separation and access based on project/partner
-Easy report generation for standard project reporting and customer-designed dedicated reports
-Stable export of data to be shared with customers

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