Review of Cresset European User Group Meeting June 2012

Our scientific programme reflected the wide range of scientific fields involved in drug discovery and the depth of breadth of scientific knowledge that goes into developing software for in silico research. The talks ranged from the force fields involved in protein-protein interactions to the use of NMR technology to understand drug metabolites. Below is a review of each presentation. If you would like further details of any presentation please contact us.

Dr Jon Mason of Heptares opened the day’s scientific talks with an informative overview of his work on the energetics of water networks in proteins. Having worked in this field for over 25 years, he has reached a point where he has found that the computational mapping of water energetics in a protein target has a high correlation with druggable binding sites for targets, or at least with ligandable targets.

Dr Mark Mackey, Cresset’s Chief Scientific Officer gave an overview of the new science that Cresset has been working on, including how conformations are generated, new sampling methodology for 3D QSAR, advances in fragment growing technology with the option to merge results from multiple ligands, and finally an updated force field, FF3 which refines and improves Cresset’s existing XED force field. He also introduced forgeV10, Cresset’s new 3D QSAR environment.
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Dr Peter Ertl, Director of Cheminformatics at Novartis shared his Intelligent Automated DEsign (IADE) method for bioisosteric design. His automated fragment replacement system firstly identifies bioisosteric fragments for a given compound and replaces them iteratively to generate several hundred analogs. These are converted to 3D structures using CORINA. Reasonable conformations are generated using Cresset software and the conformation most similar to the target is identified using FieldAlign. He used this method to design the winning molecule in Cresset’s ‘Design a Molecule’ competition in October 2011.

Dr Andy Vinter, Cresset’s Chairman updated us on how he has used the XED force field to normalise proteins and gain insights into the actions of agonists and antagonists. He reminded us that atomic charges do not sit on the nucleus, as some force fields approximate, but rather the real electrostatic charge varies close to the atom, as reflected in Cresset’s unique FF3 force field.
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Drug repositioning is an increasingly popular area of drug discovery. The increasing costs of R&D and decreasing return on investment has lead many companies to focus on finding new opportunities based on existing drugs and their templates. Dr Alan Rothaul gave an overview of structure and non-structure based methods of repositioning and showed how structure based re-profiling through fragment swapping can feed into new compound discovery. He pointed out that new intellectual property has to be established and that this is often determined through reformulation.
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Dr Ute Gerhard of the University of Hertfordshire demonstrated how the power of NMR and mass spectrometry analysis are used to determine the structure and concentration of drug metabolites. The detection limits for state of the art NMR are now where mass spectrometry was ten years ago. NMR can be used to successfully identify potentially toxic metabolites so that only good quality drug candidates are progressed through the discovery process.
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Optibrium and Cresset recently announced a collaboration to combine the power of Optibrium’s StarDrop with Cresset’s FieldAlign. Dr Matthew Segall of Optibrium gave an overview of multiple parameter optimization (MPO) for drug discovery, as delivered in StarDrop. Drug discovery demands that chemists make confident decisions based on complex multi-dimensional data. The challenge is to optimize the vast quantities of data available, while making allowances for data accuracy and weighting.
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Dr Ronnie Palin of Redx Pharma gave an overview of their approach to drug discovery by discussing novel lead identification using similarity scores. He explained the best starting point is existing drugs since they are known to hit the target and the majority of the optimisation has been done. Their Redox Switch technology is used to change the chemical structure, then Cresset FieldAlign was used to rank the Redox Switch ideas to give the rapid identification of hits in unexploited IP space. Based on this work they have filed patents in multiple therapeutic areas. He gave the example of changing carboxylic acids while retaining activity. Their anti-viral project started with the known anti-flu compounds zanamivir, oseltamivir and peramivir. Their chemists generated ideas to replace the carboxylic function, then Cresset data was used to score the results and the best results were optimized. The found good correlation between the predicted binding and the inhibition of neuraminidase.
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Dr Raj Gosain of the University of Southampton told us about two recent projects that his students have carried out using Cresset software to virtually screen compounds of interest against the ZINC database of screening compounds. In the first case a student started from an unusual squaramide structure, which when it was run through the database identified a new compound that whilst having lower activity was actually a more selective hit. Dr Gosain pointed out that they could not have arrived at this compound with any method other than Cresset software. The second example was looking for an inhibitor of the anthrax lethal factor. Starting from a compound with little potential IP due to existing patents they were able to find a tractable starting point for medicinal chemistry, which had novel structure and was clear of existing IP.

This stimulating mix of talks covered an engaging mix of disciplines including pharmacology, medicinal chemistry and computational chemistry. Dr Rob Scoffin, CEO of Cresset summed up the day by reviewing how Cresset has grown and changed over the last year: “Cresset’s customer base is expanding, there has been rebranding with new product names and organizations. However, our core focus remains the same: to provide the best science with the best customer support”.

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