Our 8th European user meeting offers a programme which is rich in scientific presentations together with training on Cresset’s products.
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.
There is no charge to attend the meeting.
|09:00||Welcome||Dr. Robert Scoffin, Cresset|
|09:15||Case study: Collaborative services project||Dr. Martin Slater, Cresset|
|09:45||Adventures in academic drug discovery
||Dr. Caroline Low, Caroline Low Drug Discovery|
|10:15||New features in Cresset’s products
||Dr. Tim Cheeseright, Cresset|
|11:00||Selectivity mining – multiple activities in Activity Miner||Dr. Martin Slater, Cresset|
|11:30||Using waterswap to predict and understand binding affinities||Dr. Christopher Woods, University of Bristol|
|12:00||Comparing the electrostatic properties of protein active sites and other Cresset research||Dr. Mark Mackey and Dr. Susana Tomasio, Cresset|
|13:45||Identification of novel potential anti-cancer agents using network pharmacology based computational modelling||Dr. Ben Allen, e-Therapeutics|
|14:15||Knowledge-based chemical fragment analysis in protein binding sites
||Dr. Edith Chan, University College London|
|14:45||CADD & ENAC – A bad hand at Scrabble?||Dr. Peter Hunt, Optibrium (formerly Novartis)|
|15:45||Panel discussion: Deploying modelling tools to medicinal chemists||Dr. Mike Bodkin, Evotec; Dr. David Livermore, Takeda; Dr. Martin Quibell, MAQU Chemistry Consulting; Dr. Chris Swain, Cambridge Med Chem Consulting|
|16:30||Torch for medicinal chemists
||Dr. Tim Cheeseright, Cresset|
|16:45||Discussion and closing remarks|
|17:15 – late||Social|
Dr. Drew Rowan, Newcastle University; Dr. Martin Slater, Director of Consulting Services, Cresset
Cresset has great science which has underpinned the software that we have produced over the last decade. Throughout this time we have also engaged in consulting work using both the commercial software, such as Blaze for virtual screening but also non-commercial software; for instance – protein minimisation using the XED force field – which we reserve in-house for detailed protein-ligand interaction work. In this presentation we will show how we have worked collaboratively both with Newcastle University and an assigned chemistry CRO to assist the project by providing the molecular modelling support for a novel Serine protease target.
Dr. Caroline M. R. Low, Consultant, Caroline Low Drug Discovery
Academic institutions are investing in technologies to translate their new biological discoveries into novel therapeutics. Our recent paper showed that UK researchers use computational design and phenotypic screening approaches to a much greater extent than their US counterparts.1 I will use examples from the project portfolio built at Imperial College’s Drug Discovery Centre to discuss the role that these approaches have played in creating tool compounds for a range of therapeutic targets. In particular I will illustrate ways in which Cresset field points played a role in advancing projects in oncology, cardiovascular and respiratory medicine.
1 Tralau-Stewart, C., Low, C.M. & Marlin, N. UK academic drug discovery. Nature reviews. Drug discovery 13, 15-16 (2014).
Dr. Tim Cheeseright, Director of Products, Cresset
We have introduced significant new functionality to our desktop applications in the last 12 months including the new activity miner module for Torch and Forge, reagent databases for Spark, and a REST interface for Blaze. In this presentation I will introduce the latest developments in all our applications and outline the role of the customer in delivering the new functionality. I will show how a good discussion between the customers and Cresset results in major pieces of functionality such as the Spark reagent databases, the REST interface to Blaze, or the Selectivity Cliffs in Activity Miner. I will include a look at the latest versions of Forge and Torch (10.3) showing as much of the new functionality as I can. Lastly I hope to outline some of the features that we are considering for future releases.
Dr. Christopher Woods, Research Scientist, University of Bristol
Waterswap is a method that allows for direct calculation of absolute protein-ligand binding free energies. The method models the protein and ligand with full flexibility, and includes a complete, explicit model for water. Waterswap works by calculating the difference in free energy between the ligand bound to the protein, and a similarly-sized cluster of water molecules bound to the protein. The binding free energy can be decomposed to per-protein-residue and per-water-molecule components, allowing visualisation of the contribution to binding from binding site residues and active site water molecules.
Dr. Mark Mackey, Chief Scientific Officer, Cresset; Dr. Susana Tomasio, Computational Chemistry Developer, Cresset
We have had a long standing interest in the application of our core technologies and ligand methods to proteins. In this presentation I will outline our progress with describing the electrostatic properties of protein active sites both for use in virtual screening and for structure based design. I will also detail the work we have been doing with 3D RISM and other research topics that we hope to conclude and release in the coming months.
Dr. Ben Allen, Computational Research Scientist, e-Therapeutics
Network pharmacology models cells as networks of interacting proteins. Within this paradigm, a disease state is identified as a disorder of large-scale sub-networks, and the target for pharmacological intervention becomes a set of proteins. Network modelling can be used to identify a set of key interactions which can be targeted to correct the network disorder. The chemoinformatic problem is then to identify compounds with desirable interactions with the set of proteins; multi-target drugs.
At e-Therapeutics we have developed a workflow based on this model, using a combination of open-source and proprietary databases and in-house proprietary chemoinformatics tools. Our current lead anti-cancer asset, dexanabinol, was identified from its network interactions, and is now completing Phase I clinical trials. Using dexanabinol’s properties and its interactions with the network of cancer related proteins in the cell as a template, this approach has been used to identify a further set of novel anti-cancer compounds. 85 compounds have been tested against a panel of 3 cancer cell lines, and 51 show some activity at the 100µm level, with 15 active at below 15µm. These results demonstrate that the network pharmacology approach is capable of generating significantly enriched sets of compounds, and is a valuable tool for early stage drug discovery.
The next stage in this project is to expand the screen, and to compare the network approach with structural similarity based compound identification. For this, dexanabinol was used as a template for a computational screen using Cresset’s Blaze tool, and 200 compounds were identified by this approach. An additional 125 compounds were generated from the network approach, together with 75 closely related analogues of hits from the first screen, and these 400 compounds are currently being sourced and tested. Once these results are available we will be able to assess the relative merits of the two methods.
Dr. Edith Chan, Computational Scientist, Wolfson Institute of Biomedical Research/UCL
We present an analysis of chemical fragments from lead-like ligands in the Protein Data Bank (PDB) that form hydrogen bonds to either main or side chains of amino acids in protein binding sites. A fragment is defined as the largest ring assembly containing the atoms involved in hydrogen bond(s) to the protein. Some case studies will be present. For example, a total of 462 unique fragments were found in 2,038 unique ligands from over 8,000 protein ligand structures in the PDB that form hydrogen bonds to the side chains of Asp, Glu, Arg, and His. Some fragments are observed to interact with Asp but not with Glu, and vice versa, despite these side chains share the same chemical moiety. Our finding of chemical fragment provides information that is useful for drug design, especially in the area of fragment-based design, chemical library design, and selection of screening compounds.
Dr. Peter Hunt, Director of Computational Chemistry, Optibrium (formerly Novartis)
Cystic Fibrosis is a disease caused by genetic defects in the CFTR protein. The manifestation of those defects in the lung is a reduction in airway hydration producing a viscous mucal layer and ineffective mucocilliary clearance leading to pathogenic build up in the lungs. The various approaches taken to develop inhibitors of the Epithelial Sodium channel (ENaC) will be described as well as the recent developments in the structural elucidation of the related family member ASIC.
Dr. Martin Slater, Director of Consulting Services, Cresset
Activity Miner is new and innovative product from Cresset allowing the visualisation of 3D field similarity activity cliffs. This addition to Forge is a superb way of navigating through the SAR of a medium sized data set – 200 cpds +. In this talk I will present the use of this application to rapidly visualise and navigate through both activity and selectivity data for a specific example from published literature data. I will show how some specific field features highlighted by this technique can relate to protein ligand interaction events.
Dr. Tim Cheeseright, Director of Products, Cresset
Following our panel discussion on deploying modelling tools to medicinal chemists, I will outline recent changes in Cresset’s Torch application which is aimed directly at medicinal chemists. I will highlight where Torch fits with any ideas put forward during the panel discussion and present our current thinking on the future of Torch.
|Workshops for medicinal chemists:||Workshops for computational chemists:||Advanced workshops for computational chemists:|
|09:00||Designing molecules in 3D – getting started with Torch and an overview of Activity Miner||Understanding SAR through electrostatics and shape with Forge||Advanced features in latest releases|
|11:00||Better bioisosteres – getting started with Spark
||Broadening your IP space with Spark||Advanced features in latest releases|
|12:30||Lunch and close|
Once again we return to the delightful setting of Madingley Hall, Madingley, Cambridge, CB23 8AQ, UK.
A limited number of bedrooms have been reserved for those attending the meeting at the rate of £68 including breakfast. Accommodation should be booked directly with Madingley Hall; contact details and the reference to quote will be provided in your registration confirmation.