This meeting is primarily designed to address the needs of Cresset software and Discovery Services users, however, non-users are welcome to attend. You will hear from existing customers and understand more about how Cresset solutions can increase the effectiveness of your discovery programs.
|8:00||Registration, breakfast and networking|
|8:15||Welcome by meeting Chairman||Tim Cheeseright, Cresset|
|8:30||From FieldScreen to Activity Miner: One Decade of Cresset Software at Boehringer Ingelheim Pharma GmbH & Co.KG||Bernd Beck, Boehringer Ingelheim|
|9:00||Advances in Structure-based Design Methods at Cresset||Mark Mackey, Cresset|
|9:30||Analyzing Building Blocks Diversity for DNA Encoded Library Design||Nikolaus Stiefl, Novartis|
|10:00||Break and networking|
|10:30||What’s New in Cresset Software Including Our Upcoming Structure-based Design Application||Tim Cheeseright, Cresset|
|11:00||The Open Innovation Drug Discovery (OIDD): Virtual Screening – Mining Blindly||Mark Mackey, Cresset (on behalf of Maria Alvim-Gaston, Eli Lilly)|
|11:15||Case studies: Cresset Software Applied by Cresset Scientists||Mark Mackey and Tim Cheeseright, Cresset|
|11:30||Mapping Diversity in 3D Space Using Cresset Field Alignments||Patrick McCarren, Broad Institute|
Bernd Beck, Boehringer Ingelheim
In 2004 the Computational Chemistry group in Biberach started to evaluate different pharmacophore tools. In the course of this evaluation we also invited Cresset BioMolecular Discovery Ltd to present their product Fieldscreen (now known as Blaze). In December 2004 we start the evaluation of the software. After a few initial difficulties we test the product and finally decide to use FieldScreen as one of our virtual screening tools. Since then a lot of very successful virtual screening campaigns were performed using FieldScreen. In the last few years the focus shifted more and more away from virtual screening campaigns in existing compound collections (intern or extern) to answer more specific questions within a lead optimization project like property or activity predictions (Model generation in Forge), visual support of the SAR analysis (Activity Miner in Forge) or bioisosteric replacement (Spark). In the presentation the usage of Cresset software within Boehringer Ingelheim Pharma will be summarized and illustrated with several examples for the different application scenarios.
Mark Mackey, Cresset
For the last decade Cresset has been known for its excellent ligand-based modeling techniques, focussing on the electrostatics and shape of small molecules. While developing and improving our techniques for describing and modeling these, we have always kept an eye on proteins, looking for new ways to apply our proprietary science. In the last couple of years we have presented our results in this endeavour, primarily focussing on protein fields.
This year we will show our further progress on the protein fields front, including comparisons to our new small-molecule modeling technique Activity Atlas. We will also show the latest results validating our approach to water modeling with 3D-RISM against quantum mechanical results, as well as giving an introduction to the WaterSwap technique for which we intend to provide the first commercial implementation.
Nikolaus Stiefl, Novartis
Rooted 2D fingerprints and modified invariant fingerprints in conjunction with 3D cresset fields combined with exit vector alignment were developed to create a building blocks diversity selection process for DNA Encoded Libraries. Using modified 2D fingerprints allows for an efficient description and classification of building blocks taking into account the specifics of reacting groups. Furthermore, Cresset fields clustering enhances the selection by enriching sets for building blocks distributing fields as evenly as possible in space to address future protein targets and create SAR information.
Tim Cheeseright, Cresset
We will be showing and discussing all the improvements that have been introduced to our software over the last year and briefly discussing the roadmaps for the released software. However, much of our presentation will focus on the latest alpha version of our structure-based design application. We will describe the architecture of the new application and its potential benefits as well as receive live feedback. The application will be used to demonstrate some of the techniques discussed in Mark’s talk including viewing protein-ligand interactions, protein electrostatics and 3D-RISM. We aim to discuss all aspects of the application including its docking performance on standard test sets. The application will be available for attendees to use during breaks and in the supplementary workshops. Feedback is welcomed on the current state of development as well as future feature requests.
Mark Mackey, Cresset (on behalf of Maria Alvim-Gaston, Eli Lilly and Company)
Maria Alvim-Gaston*, Gregory Durst£, and Marta Pineiro-Nunez*
*Open Innovation Drug Discovery, Discovery Chemistry; £ Computational Chemistry and Cheminformatics, Discovery Chemistry
The Open Innovation Drug Discovery (OIDD) program at Eli Lilly offers to examine submitter’s molecules for suitable drug properties and to direct molecules to various assays without directly reviewing chemical structures, thus maintaining structural confidentiality with our clients. This is done by calculating 2D and 3D molecular fingerprints for each submission and passing only those fingerprints on for making decisions. This is straight forward for 2D fingerprints, but presents a challenge for 3D fingerprints. Cresset’s standard 3D similarity score is computed as a weighted average of 3D shape similarity and field similarity. The standard weighting is 50-50 and the field points are usually represented around the 3D structure. This standard representation is not appropriate in the OIDD context. In the OIDD case we calculate and pass on only the field points and sizes with the explicit structure information removed from the file. This field point only file is a 3D abstraction of the submitted molecule, but it proves a suitable and useful construct to compare to other molecular field point files for making further decisions. With this metric, only the field points of the candidate molecule need to be transmitted across the OIDD firewall, meeting the confidentiality requirements. The application of this modified metric within the OIDD Virtual Screening initiative will be discussed.
Mark Mackey and Tim Cheeseright, Cresset
Case studies are an important component of the scientific validation work at Cresset, where the retrospective analysis of published projects is used to probe and prove the scientific applicability of our methods to drug discovery problems. Ideally, they should also suggest to our users less obvious ways to use our software to support the daily activities of their project. Case studies are also important to showcase the new capabilities of our software to our new, prospective and historical users.
In this presentation I will provide an overview of the most recent and interesting case studies published on the Cresset website using Spark, Forge/Torch and Blaze capabilities. In particular, I will show how the newly released Spark fragment and reagent databases can be used in unconventional bioisostere replacement experiments, such as fragment growing, linking, macro-cyclization and water replacement. I will also illustrate the combined use of Forge’s Activity Atlas and Activity Miner for deciphering complex activity and selectivity SAR.
Patrick McCarren, Broad Institute
For novel additions to our screening library from commercial sources, we have recently been investigating 3D diversity measures using Cresset field and shape similarity. Though this is challenging computationally, mapping in this space generates interesting results different from 2D and simple 3D descriptors. The method and comparison of its results to simpler 3-dimensional descriptors such as principal moments of inertia plots, 2D diversity, and activity diversity will be presented.
Dr Bernd Beck studied chemistry at the University of Erlangen in Germany. He did his PhD thesis in the research group of Prof. Timothy Clark at the University of Erlangen in collaboration with the Wellcome Research Laboratories in Beckenham (London). He obtained his PhD in Organic Chemistry at the beginning of 1996. After PostDocs in Physical Chemistry at the University of Jena and in the Computational Chemistry Centre at the University of Erlangen he joined Oxford Molecular to develop new chemoinformatics software tools. At the end of 2001, he joined the chemoinformatics team of Boehringer Ingelheim. In addition to supporting CNS research projects, he currently heads an international project team to establish a new data analysis and visualization tool for research data in the global research organization. His research interests include molecular modelling, lead generation/optimization and chemoinformatics, especially data mining.
After a DPhil in Chemistry at the University of Oxford, Tim gained experience as both a medicinal chemist and a molecular modeler at Peptide Therapeutics and Medivir. Tim joined Cresset in 2002. As Director of Products he is responsible for delivering easy to use applications that solve key problems in small molecule drug design and discovery.
Mark graduated from the University of Tasmania in 1992 with a BSc in Chemistry, Physics and Mathematics. Between 1988 and 1992 Mark was awarded the following accolades: Chemistry Honors Prize at University of Tasmania; Dean’s citation for outstanding undergraduate and Honors achievements; University Medal from University of Tasmania; ICI Australia Ltd Prize for third year chemistry; Masson Memorial Prize for top chemistry graduate in Australia.
In 1993 Mark moved to the University of Cambridge where he was awarded his PhD in 1997. It was during his time at Cambridge that Mark first worked with Dr Andy Vinter, founder of Cresset.
Upon completion of his PhD Mark worked as a Molecular Modeler and Senior Research Scientist for Napp Pharmaceuticals and Merck Sharp & Dohme respectively.
In 2002 Dr Vinter invited Mark to join him as a founder member of Cresset. Mark has designed and added fundamental science to tools that are now accepted and used by many pharmaceutical, agrochemical and academic institutions across the world. In 2010 Mark was appointed as CSO of Cresset.
Dr Patrick McCarren graduated with degrees in chemistry and physics from Ohio State University in 2000 with an undergraduate thesis on oligosaccharide synthesis and biasing conformational preferences of furanoses (5-membered ring carbohydrates). This synthetic and NMR spectroscopy work led into a Research Scientist position investigating the preferences computationally. Patrick went on to receive his Ph.D. in organic chemistry from UCLA in 2009 using quantum mechanics to study mechanisms of nitric oxide signaling and organometallic reactions through an NIH Chemical Biology training fellowship. Since then, his work has been focused on using computational chemistry in drug discovery first during an industry postdoc at Novartis in 2009, and currently as a computational chemist in the Broad Institute’s Center for the Development of Therapeutics since 2012 working mostly on oncology, infectious disease and cardiovascular targets.
Nik Stiefl studied pharmacy from 1993 until 1999 in Würzburg. He obtained his PhD in the lab of Knut Baumann in Wuerzburg in 2004, after an internship in GlaxoWellcome in Stevenage. His main focus then was QSAR and molecular descriptors as well as statistical validation.
Nik Stiefl worked as a postdoctoral fellow in Eli Lilly and Co. for a year focusing on the implementation and application of reduced graphs for virtual screening in drug discovery.
He then started in Novartis in Basel in 2005 and is supporting medicinal chemistry projects as a modeler and cheminformatician and has a track record of successful compounds brought to candidate selection process for POC studies. Nik has also co-developped as project leader a globally integrated desktop visualization and communication tool to facilitate idea exchange between chemists and modellers (FOCUS).
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