This meeting is primarily designed to address the needs of Cresset customers, however, non-users are also welcome to attend. You will hear from existing customers and understand more about how Cresset solutions can increase the effectiveness of your discovery programs.
In our industry, where confidentiality is so important, it is a mark of respect for each other that we manage to share the inspiration and ideas behind our common scientific goals in a constructive way. As has been the case at previous Cresset user meetings, we once again look forward to the open sharing of ideas, approaches and results.
|9:00||Registration, refreshments and networking|
|9:45||Welcome by meeting Chairman||Rob Scoffin, Cresset|
|10:00||From FieldScreen to Activity Miner: One Decade of Cresset Software at Boehringer Ingelheim Pharma GmbH & Co.KG||Bernd Beck, Boehringer Ingelheim|
|10:30||Advances in Structure-based Design Methods at Cresset||Mark Mackey, Cresset|
|11:00||Break and networking|
|11:30||Prediction of Cyclic Peptide Passive Permeability||Sandeep Pal, GlaxoSmithKline|
|12:00||What’s New in Cresset Software Including Our Upcoming Structure-based Design Application||Giovanna Tedesco, Cresset|
|12:30||Lunch and networking|
|1:45||In Silico Analysis of Inhibitor Interactions with Efflux Pumps and their Substrates: An Alternative Approach to Overcoming Multidrug Resistance||Mire Zloh, University of Hertfordshire|
|2:15||Analysing Building Blocks Diversity for DNA Encoded Library Design||Finton Sirockin and Nikolaus Stiefl, Novartis|
|2:45||Introduction to Docking with Lead Finder||Susana Tomásio, Cresset|
|3:05||Case studies: Cresset Software Applied by Cresset Scientists||Tim Cheeseright, Cresset|
|3:30||Break and networking|
|4:00||Tioxazafen, a New Broad-spectrum Seed Treatment Nematicide||Matt Dimmic, Monsanto|
|4:30||Uses of Field Similarity in Library Design and Sidechain Enrichment||David Evans, Eli Lilly|
|5:00||Design of a Focussed CNS Screening Collection at Takeda||David Livermore, Takeda|
|5:30||Closing remarks||Rob Scoffin, Cresset|
|6:00||Drinks reception: The prediction|
|7:00||Dinner: An extraordinary revelation|
Choose up to 4 sessions to attend. Further details about the content of each workshop are provided below to help you choose the right workshop for you.
Spaces are limited so register now to secure your place.
Who should attend: Established Forge users comfortable with aligning molecules.
Explore the advanced options in Forge that will transform you into a power user. Topics include advanced alignment options, calculating new columns in the molecule table, updating the molecule table with new data, useful keyboard shortcuts, filtering of data within the molecule table and rapid model exploration.
Who should attend: Computational, medicinal and synthetic chemists who use computational tools regularly. Some familiarity with alignment in Forge or Torch would be an advantage.
Using the Activity Atlas models and the Activity Miner interface of Forge, explore how to rapidly decipher the SAR of a series of molecules. It will highlight an efficient workflow, detail how to identify outliers and generate meaningful summaries of SAR for use in molecular design in Torch or Forge.
Who should attend: Computational chemists. Some familiarity with alignment in Forge or Torch would be an advantage.
Using Forge we introduce Cresset’s methods for developing 3D and 2D-QSAR models. We will show how to: build multiple models and choose between them; interpret 3D-QSAR models; use the models to predict activity for new compound design; use the visual feedback to improve compound design.
Who should attend: Medicinal, synthetic and computational chemists with no experience of Cresset applications.
Learn to quickly generate novel ideas and bioisosteres for molecule cores and R-groups using Spark. We will introduce the standard functionality of Spark with an emphasis towards new users. It will cover the choice of databases to search, how to link searches and results to available databases, visualization and interpretation of results and selection/tagging/filtering of best molecules to progress.
Who should attend: Medicinal, synthetic and computational chemists. Some familiarity with Spark would an advantage.
Explore the advanced options in Spark that will transform you into a power user. Topics include using excluded volumes and field point constraints to incorporate relevant protein information in the search; advanced search options, including use of substructure filters; how to set-up fragment growing and water replacement experiments.
Who should attend: Medicinal, synthetic and computational chemists with some experience of Spark.
Explore the latest features in Spark 10.4 including the new processing dialog, substructure filtering, multi-parameter optimization scoring and the new reagent and fragment databases.
Who should attend: Medicinal, synthetic and computational chemists with no experience of Cresset applications.
You will learn to use electrostatic and shape properties to understand the wider implications of molecular design; ensure that new designs make sense in 3D; and use electrostatics to add greater novelty to your projects. You will learn to optimize more than potency using a single scoring function that represents the fit of your new designs to your project profile.
Who should attend: Medicinal, synthetic and computational chemists with some experience of Torch.
Learn to exploit the advanced features of Torch to improve collaborative communication, search for and understand activity cliffs and use these in the design of new molecules. Discover how to interrogate a dataset using filters, molecule roles, tags and plots. Maximize your productivity with keyboard shortcuts and communicate your findings effectively with export functions.
Who should attend: Computational, medicinal and synthetic chemists interested in finding new hits through virtual screening.
Learn to use Blaze Cloud to find new hits and leads for your project. See how to interface Forge to Blaze to enable search submission and result retrieval from within Forge. Learn to identify the optimal set of query molecules and how best to combine results. See how the use of constraints and protein excluded volumes can focus the results towards the compounds with the highest probability of success.
Who should attend: Computational, medicinal and synthetic chemists with an interest in structure-based design.
We will introduce the latest development snapshot of our new structure-based design product. See the alpha in action, learn how it will use the Cresset force field to analyze and visualize the electrostatic features of protein active sites, analyze water positions and energetics or docked ligands.
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 tested 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 (internal or external) 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.
Sandeep Pal, GlaxoSmithKline
Passive permeability of cyclic peptides depends on intra-molecular hydrogen bonding (H-bonding) and lipophilicity. Intra-molecular H-bonding facilitates passive membrane permeability by masking polarity of a compound in the non-polar ‘membranephilic’ environment. In addition to the polarity of a compound, lipophilicity and size affect passive membrane permeability. For compounds with smaller molecular weight (MW < 400 Da), it is possible to extract meaningful topological descriptors (‘2D descriptors’) relating to polarity, lipophilicity and size of a compound, which could explain passive permeability. On the other hand, for compounds with larger molecular weight (MW > 500 Da), the dependence of polarity on intra-molecular H-bonding is higher and therefore harder to extract meaningful 2D descriptors (relating to polarity) for such compounds. Predicting intra-molecular H-bonding adds an extra level of complexity to the problem of predicting passive permeability. Therefore it is difficult to obtain a predictive model for passive permeability for compounds with a range of molecular weights. It has been reported elsewhere that for compounds with higher molecular weights (~ 400 Da), passive permeability and oral absorption can be achieved by mainly increasing lipophilicity of the compounds. In this presentation I attempt to see the validation of this hypothesis in a congeneric series of cyclic peptides. A two component classification based model (Partial Least Squares Discriminant Analysis, PLS-DA) that classifies compounds (Small molecular drugs and peptides) as permeable or non-permeable is reported in this presentation. Such classification based models are routinely used within pharmaceutical industry to optimize passive permeability and eventually oral bioavailability of a compound. Using ChromlogD as a lipophilic descriptor and Solvation energy as a 3D descriptor I attempt to derive a common discriminant model for small molecule drug compounds (marketed drug compounds) and cyclic peptides. The dataset includes 111 marketed drug compounds and 14 cyclic peptides with passive permeability measured within GSK and reported in the article.
Giovanna Tedesco, Cresset
I 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 the presentation will focus on the latest alpha version of our structure-based design application. I 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. I 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.
Mire Zloh, University of Hertfordshire
Multidrug Resistance (MDR) is a growing problem and occurs in part due to the over-expression of efflux pumps responsible for the removal of therapeutics from cells. Preventing drug efflux can be achieved by a range of structurally unrelated compound, but the major challenge is a discovery of safe and efficacious agents. We have used complex formation between efflux pump substrates and escort molecules as a criterion for the development of an in silico screening method for molecules that are able to restore activity of therapeutics against MDR species. A combination of molecular similarity searches and the docking procedure that utilizes molecular interaction fields generated by GRID were used for the selection of potential escort molecules. Using our approach, within the 2396 molecules available in the SUPERDRUG database we distinguished three molecules with already proven ability to act in synergy with antibiotics and discovered two molecules that modulate the efflux pumps. This approach is used to query other databases of molecules and it has the potential to be utilized for the discovery of ‘escort’ molecules for other drugs that are effluxed by multidrug-resistant cells. The challenge of predicting small molecule – small molecule complexes will be discussed.
Finton Sirockin and 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.
Susana Tomásio, Cresset
Understanding the interactions between proteins and ligands is crucial for the design and optimization of new molecules. Although the development of molecular docking methods has been underway for a few decades, its accuracy is still far from satisfactory.
Several criteria are typically used to evaluate the accuracy of a docking method, such as the accuracy of the prediction of the ligands pose in a protein-ligand complex, the accuracy of the ligand binding affinity prediction and the accuracy in virtual screening. In this talk, I look at these criteria present the molecular docking software Lead Finder which is being implemented in our upcoming structure-based design application. I will also focus on the theoretical aspects of sampling and scoring. Finally, the performance of Lead Finder will be evaluated with the well-known Astex and DUD test sets.
Results show that Lead Finder performs well on ligand docking and on screening large ligand libraries, showing good early enrichment values.
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.
Matt Dimmic, Monsanto
Tioxazafen is Monsanto’s new seed treatment nematicide that is designed to provide consistent broad spectrum control of parasitic nematodes in corn, soy and cotton. This new class of nematicide chemistry, the 3,5-disubstituted-1,2,4-oxadiazole class, has demonstrated excellent activity in greenhouse and field trials. The talk will describe the discovery process and review the use of molecular modeling for agrochemical discovery.
David Evans, Eli Lilly
The Cresset suite of tools has been used extensively at Lilly for several years for virtual screening and sidechain replacement. Recently the Spark tool has been integrated in our process for library design on the Automated Synthesis Laboratory. We will present use cases, and analysis of the enrichment provided by the use of field similarity will be discussed alongside examples of isosteric replacements that have been found in the prospective use of the tool.
David Livermore, Takeda
Identification of molecules capable of crossing the blood-brain barrier is challenging1,2. Analysis of the physicochemical properties of marketed CNS drugs shows that they typically have lower molecular weight, polar surface area and molecular flexibility compared to marketed non-CNS drugs3.
Takeda has identified CNS diseases as an important research therapeutic area for the future. In order to ensure the best possible potential starting-points from HTS screening, we have sought to enhance the diversity of its compound collection in CNS chemical space.
Identifying commercially available molecules which meet strict CNS criteria whilst adding to the diversity of the overall collection has proved difficult. Therefore, we developed the Centrally Accessible Molecules (CAMs) library which has been designed and synthesised at Takeda Cambridge over the last few years. In this presentation, the design principles behind the creation of the CAMs library, which has led to a number of promising chemotypes for current CNS projects, will be discussed.
1 M.S. Alavijeh, M. Chishty, M.Z. Qaiser, A.M. Palmer, Journal of the American Society for Experimental. Neurotherapeutics, 2005, 2, 554
2 Z. Rankovic, J Med Chem, 2015, 58, 2584
3 T.T. Wager, R.Y. Chandasekaran, X. Hou, M.D. Troutman, P.R. Verhoest, A. Villalobos, Y. Will, ACS Chem. Neuroscience, 2010, 1, 420
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 modeling, 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.
Matt Dimmic received his PhD in Biophysics from the University of Michigan, and holds undergraduate degrees in Biology and Chemistry. In 2005 he joined the biotech startup Divergence, where he developed their computational chemistry pipeline and researched new methods for controlling parasitic nematodes and fungal pathogens. In 2011 Divergence was acquired by Monsanto, where Matt now leads the Computational Biology Platform in the Chemistry Technology division.
David Evans studied at Cambridge, receiving a PhD in computational studies of peptide folding and dynamics in the group of David Wales. He worked on DNA binding ligands for Spirogen, before joining Lilly where he is a computational chemistry group leader and works across several target classes and therapeutic areas in support of ongoing medicinal chemistry projects.
Following a BSc and PhD in Organic chemistry at Imperial College, London, David took up the role of medicinal chemist at Glaxo. In 1995 he moved to the GlaxoWellcome/GSK cardiovascular team in Stevenage, then in 2003 to GSK Harlow in a dual role of medicinal chemist/computational chemist – neurology. Since 2010, David has headed up the computational chemistry team at Takeda in Cambridge.
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.
Sandeep did his PhD in chemistry from Max Planck Institute for Polymer research in Germany in the field of Material science. His postdoctoral research work was in the area of prediction of protein-protein complexes using molecular dynamics simulations. Sandeep then worked under Dr David Leahy at the Northern Institute for Cancer research mainly developing cheminformatics software for small molecule 3D similarity using shape and pharmacophore. This code was written using Chemical Descriptor Library. From 2008 till 2011 he worked in the computational chemistry team at Evotec, working on several medicinal chemistry projects involving GPCRs. Sandeep is now part of the computational and modelling sciences group at GSK.
Dr Robert Scoffin is an experienced entrepreneur and senior executive within the life sciences software industry. Following a DPhil gained from Oxford University, he worked for eight years at Oxford Molecular, seeing the company grow from 15 to 250 people and a successful floatation on the London Stock Exchange.
In 1998 Rob joined CambridgeSoft, at the time a well-known creator of desktop chemistry software, with the remit to help grow an Enterprise Informatics business with particular focus on the European market. He achieved great success with CambridgeSoft over a twelve year period, managing European Operations with responsibility for marketing, sales, support and professional services. Rob oversaw the growth of the business to more than $18m in annual turnover, being responsible for a team of more than 30 direct employees and more than 65 contract staff.
Rob joined Cresset as CEO in 2010. During the time he has been leading the team, Cresset has further developed its software and services from a very solid customer base, into a high-growth and profitable business.
In 2014 Rob co-founded Re-Pharm, an early-stage drug discovery and development company based on the principles of compound re-profiling.
Finton Sirockin studied chemistry from 1992 to 1997 in Université Louis Pasteur in Strasbourg. He obtained his PhD in Prof. Martin Karplus lab in 2003. His work involved the development of an approach integrating experimental NMR NOE constraints to postprocess fragments poses generated by multiple copy simultaneous searches (MCSS). In parallel, he developed a semi-empirical model to quantify the effect of disulfide bridges on neighbouring proton chemical shifts.
He then joined in 2003 the bioinformatics group of Prof. Mandel and Prof. Moras Institut de Génétique et Biologie Moléculaire et Cellulaire in Illkirch to work on structural biology integration to high throughput genomics approach with a grant from Généthon.
He joined Novartis in Basel in 2004 and is supporting medicinal chemistry projects as a modeler since then, with a track record of of successful compounds brought to candidate selection process for POC studies. He has and is also acting as CADD contact to various platforms in Research.
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-developed as project leader a globally integrated desktop visualization and communication tool to facilitate idea exchange between chemists and modellers (FOCUS).
Dr Giovanna Tedesco joined Glaxo in 1990. As senior computational chemist she supported a variety of drug discovery programs in the antibacterials and CNS areas, and led target-to-lead CNS programs. When Aptuit took over the GSK site in Verona, Giovanna moved to client services where she worked as a senior proposal driver.
Giovanna joined Cresset in December 2014. As product manager she has responsibility for delivering software for computational chemists.
Susana received her degree in Chemistry (Physical-Chemistry area) from the University of Coimbra, Portugal. She followed this with a PhD in Theoretical and Computational Chemistry at the University of Warwick, under the supervision of Dr Tiffany Walsh, where she studied the interactions between peptides and carbon nanotubes with a polarisable force-field. Susana then continued with a postdoc in Computational Chemical Biology at the University of Southampton under the supervision of Dr Syma Khalid. This was followed by a post-doctoral research at the University of Cambridge, UK, under the supervision of Dr Peter Bond where Susana applied free energy techniques to probe the molecular determinants of TLR4-ligand recognition and activation. As a computational chemist at Cresset Susana is involved in the research and validation of new methods to be implemented in Cresset’s software.
Professor Mire Zloh has joined Department of Pharmacy at the University of Hertfordshire in 2013. He was awarded a BSc and an MSc in Physical Chemistry by University of Belgrade and was awarded a PhD in Chemistry by University of London in 1998. Previously he was a Senior Lecturer and Director of the Centre for Structural Chemistry at the UCL School of Pharmacy. His research interests include computer aided drug design, structural chemistry and chemometrics. Currently, he is working on rational design of pharmaceutical formulations, in silico prediction of off-target activities, modeling of dendrimers and PEGylated proteins, and developing strategies to utilize small molecule-small molecule interactions for enhancing activities of therapeutics.
Granta Centre, Granta Park, Great Abington, Cambridge, CB21 6GP, UK
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Bed and breakfast is at Granta Park, Great Abington, Cambridgeshire. The accommodation is a 3 minute walk from the Granta Centre where the meeting is being held, also located on Granta Park. All rooms comprise a double bed, en-suite bathroom, desk, TV, Wi-Fi and tea/coffee-making facilities.